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1
Freitas-Lima, Leandro Ceotto, Alexandre Budu, Adriano Cleis Arruda, Mauro Sérgio Perilhão, Jonatan Barrera-Chimal, Ronaldo Carvalho Araujo, and Gabriel Rufino Estrela. "PPAR-α Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2." International Journal of Molecular Sciences 21, no. 19 (October 8, 2020): 7416. http://dx.doi.org/10.3390/ijms21197416.
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Cisplatin is a chemotherapy drug widely used in the treatment of solid tumors. However, nephrotoxicity has been reported in about one-third of patients undergoing cisplatin therapy. Proximal tubules are the main target of cisplatin toxicity and cellular uptake; elimination of this drug can modulate renal damage. Organic transporters play an important role in the transport of cisplatin into the kidney and organic cations transporter 2 (OCT-2) has been shown to be one of the most important transporters to play this role. On the other hand, multidrug and toxin extrusion 1 (MATE-1) transporter is the main protein that mediates the extrusion of cisplatin into the urine. Cisplatin nephrotoxicity has been shown to be enhanced by increased OCT-2 and/or reduced MATE-1 activity. Peroxisome proliferator-activated receptor alpha (PPAR-α) is the transcription factor which controls lipid metabolism and glucose homeostasis; it is highly expressed in the kidneys and interacts with both MATE-1 and OCT-2. Considering the above, we treated wild-type and PPAR-α knockout mice with cisplatin in order to evaluate the severity of nephrotoxicity. Cisplatin induced renal dysfunction, renal inflammation, apoptosis and tubular injury in wild-type mice, whereas PPAR-α deletion protected against these alterations. Moreover, we observed that cisplatin induced down-regulation of organic transporters MATE-1 and OCT-2 and that PPAR-α deletion restored the expression of these transporters. In addition, PPAR-α knockout mice at basal state showed increased MATE-1 expression and reduced OCT-2 levels. Here, we show for the first time that PPAR-α deletion protects against cisplatin nephrotoxicity and that this protection is via modulation of the organic transporters MATE-1 and OCT-2.
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Kim, Sunjoo, Won-Gu Choi, Mihwa Kwon, Sowon Lee, Yong-Yeon Cho, Joo Young Lee, Han Chang Kang, Im-Sook Song, and Hye Suk Lee. "In Vitro Inhibitory Effects of APINACA on Human Major Cytochrome P450, UDP-Glucuronosyltransferase Enzymes, and Drug Transporters." Molecules 24, no. 16 (August 19, 2019): 3000. http://dx.doi.org/10.3390/molecules24163000.
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APINACA (known as AKB48, N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide), an indazole carboxamide synthetic cannabinoid, has been used worldwide as a new psychoactive substance. Drug abusers take various drugs concomitantly, and therefore, it is necessary to characterize the potential of APINACA-induced drug–drug interactions due to the modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of APINACA on eight major human cytochrome P450s (CYPs) and six uridine 5′-diphospho-glucuronosyltransferases (UGTs) in human liver microsomes, as well as on the transport activities of six solute carrier transporters and two efflux transporters in transporter-overexpressed cells, were investigated. APINACA exhibited time-dependent inhibition of CYP3A4-mediated midazolam 1′-hydroxylation (Ki, 4.5 µM; kinact, 0.04686 min−1) and noncompetitive inhibition of UGT1A9-mediated mycophenolic acid glucuronidation (Ki, 5.9 µM). APINACA did not significantly inhibit the CYPs 1A2, 2A6, 2B6, 2C8/9/19, or 2D6 or the UGTs 1A1, 1A3, 1A4, 1A6, or 2B7 at concentrations up to 100 µM. APINACA did not significantly inhibit the transport activities of organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT)1, OCT2, P-glycoprotein, or breast cancer resistance protein at concentrations up to 250 μM. These data suggest that APINACA can cause drug interactions in the clinic via the inhibition of CYP3A4 or UGT1A9 activities.
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Sala-Rabanal, Monica, Dan C. Li, Gregory R. Dake, Harley T. Kurata, Mikhail Inyushin, Serguei N. Skatchkov, and Colin G. Nichols. "Polyamine Transport by the Polyspecific Organic Cation Transporters OCT1, OCT2, and OCT3." Molecular Pharmaceutics 10, no. 4 (March 19, 2013): 1450–58. http://dx.doi.org/10.1021/mp400024d.
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Ramotar, Dindial. "The tales of two organic cation transporters, OCT-1 and OCT-2, in C. elegans." ADMET and DMPK 5, no. 3 (September 29, 2017): 146. http://dx.doi.org/10.5599/admet.5.3.394.
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Solute carrier transporters, previously thought to perform roles in the transport of ions and various nutrients are now assigned broader functions. These transporters have recently been shown to permit entry of therapeutic drugs into cells. There is growing interest to understand the broad spectrum of drugs and chemical compounds that are recognized by these transporters such that specific ligands can be used as therapeutics to target definite physiological pathways. To facilitate this investigation, simpler and cost effective model systems are needed, one of such is the live whole model animal Caenorhabditis elegans (C. elegans) that offers a multitude of advantages. In general, studies with C. elegans are feasible due to the simplicity of the readouts that include lifespan, brood size, germ cell death, and visualization by epifluorescent microscopy, which can be set up in any laboratory. In C. elegans, two solute carrier transporters, the organic cation transporters OCT-1 and its paralogue OCT-2 have been partially characterized. OCT-1 mutants display a significantly reduced lifespan and brood size, as well as exhibiting an increased susceptibility towards oxidative stress and a subset of DNA damaging agents. These multiple phenotypes are directly linked to OCT-1 depletion causing upregulation of OCT-2, as RNAi-mediated downregulation of OCT-2 rescues the oct-1 mutant phenotypes. Thus, in C. elegans OCT-1 exerts control onto OCT-2, and this latter transporter plays a predominant role in the uptake of various ligands. We first showed that OCT-2 can efficiently mediate uptake of the widely used anticancer drug doxorubicin into the animals, but prevented uptake upon its downregulation. Additional ligands of OCT-2 including cisplatin and camptothecin were revealed by ligand-docking prediction studies. These analyses generated docking scores indicating that OCT-2 can make robust contact with a number of therapeutics and anticancer drugs, as well as chemical compounds that possess the ability to target specific physiological pathways. Several of the compounds displaying high docking scores with OCT-2 were validated and indeed found to be substrates that OCT-2 transported into the animals. This review provides an insight how the transporters OCT-1 and OCT-2 of a simple model organism C. elegans can be exploited to report on the cytotoxicities and genotoxicities of therapeutic agents, as well as trace amounts of undocumented toxic compounds with neoplastic potentials that are present in the environment.
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Mettral, Jaurès B., Nicolas Faller, Sandra Cruchon, Loïc Sottas, Thierry Buclin, Laurent Schild, Eva Choong, Aimable Nahimana, and Laurent A. Decosterd. "Imatinib Uptake into Cells is Not Mediated by Organic Cation Transporters OCT1, OCT2, or OCT3, But is Influenced by Extracellular pH." Drug Metabolism Letters 13, no. 2 (January 15, 2020): 102–10. http://dx.doi.org/10.2174/1872312813666190207150207.
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Background: Cancer cells undergo genetic and environmental changes that can alter cellular disposition of drugs, notably by alterations of transmembrane drug transporters expression. Whether the influx organic cation transporter 1 (OCT1) encoded by the gene SLC221A1 is implicated in the cellular uptake of imatinib is still controversial. Besides, imatinib ionization state may be modulated by the hypoxic acidic surrounding extracellular microenvironment. Objective: To determine the functional contribution of OCTs and extracellular pH on imatinib cellular disposition. Methods: We measured imatinib uptake in two different models of selective OCTs drug transporter expression (transfected Xenopus laevis oocytes and OCT-expressing HEK293 human cells), incubated at pH 7.4 and 6, using specific mass spectrometry analysis. Results: Imatinib cellular uptake occurred independently of OCT1- OCT2- or OCT3-mediated drug transport at pH 7.4. Uptake of the OCTs substrate tetraethylammonium in oocytes remained intact at pH 6, while the accumulation of imatinib in oocytes was 10-fold lower than at pH 7.4, irrespectively of OCTs expressions. In OCT1- and OCT2-HEK cells at pH 6, imatinib accumulation was reduced by 2- 3-fold regardless of OCTs expressions. Since 99.5% of imatinib at pH6 is under the cationic form, the reduced cellular accumulation of imatinib at such pH may be explained by the lower amount of uncharged imatinib remaining for passive diffusion across cellular membrane. Conclusion: Imatinib is not a substrate of OCTs 1-3 while the environmental pH modulates cellular disposition of imatinib. The observation that a slightly acidic extracellular pH influences imatinib cellular accumulation is important, considering the low extracellular pH reported in the hematopoietic leukemia/ cancer cell microenvironment.
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Bleasby, Kelly, Robert Houle, Michael Hafey, Meihong Lin, Jingjing Guo, Bing Lu, Rosa I. Sanchez, and Kerry L. Fillgrove. "Islatravir Is Not Expected to Be a Victim or Perpetrator of Drug-Drug Interactions via Major Drug-Metabolizing Enzymes or Transporters." Viruses 13, no. 8 (August 7, 2021): 1566. http://dx.doi.org/10.3390/v13081566.
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Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1. The potential for islatravir to interact with commonly co-prescribed medications was studied in vitro. Elimination of islatravir is expected to be balanced between adenosine deaminase–mediated metabolism and renal excretion. Islatravir did not inhibit uridine diphosphate glucuronosyltransferase 1A1 or cytochrome p450 (CYP) enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, nor did it induce CYP1A2, 2B6, or 3A4. Islatravir did not inhibit hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 2, MRP3, or MRP4. Islatravir was neither a substrate nor a significant inhibitor of renal transporters organic anion transporter (OAT) 1, OAT3, OCT2, multidrug and toxin extrusion protein (MATE) 1, or MATE2K. Islatravir did not significantly inhibit P-glycoprotein and breast cancer resistance protein (BCRP); however, it was a substrate of BCRP, which is not expected to be of clinical significance. These findings suggest islatravir is unlikely to be the victim or perpetrator of drug-drug interactions with commonly co-prescribed medications, including statins, diuretics, anti-diabetic drugs, proton pump inhibitors, anticoagulants, benzodiazepines, and selective serotonin reuptake inhibitors.
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Engelhart, Darcy C., Jeffry C. Granados, Da Shi, Milton H. Saier Jr., Michael E. Baker, Ruben Abagyan, and Sanjay K. Nigam. "Systems Biology Analysis Reveals Eight SLC22 Transporter Subgroups, Including OATs, OCTs, and OCTNs." International Journal of Molecular Sciences 21, no. 5 (March 5, 2020): 1791. http://dx.doi.org/10.3390/ijms21051791.
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The SLC22 family of OATs, OCTs, and OCTNs is emerging as a central hub of endogenous physiology. Despite often being referred to as “drug” transporters, they facilitate the movement of metabolites and key signaling molecules. An in-depth reanalysis supports a reassignment of these proteins into eight functional subgroups, with four new subgroups arising from the previously defined OAT subclade: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and Slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, and SLC22A25). We propose merging the OCTN (SLC22A4, SLC22A5, and Slc22a21) and OCT-related (SLC22A15 and SLC22A16) subclades into the OCTN/OCTN-related subgroup. Using data from GWAS, in vivo models, and in vitro assays, we developed an SLC22 transporter-metabolite network and similar subgroup networks, which suggest how multiple SLC22 transporters with mono-, oligo-, and multi-specific substrate specificity interact to regulate metabolites. Subgroup associations include: OATS1 with signaling molecules, uremic toxins, and odorants, OATS2 with cyclic nucleotides, OATS3 with uric acid, OATS4 with conjugated sex hormones, particularly etiocholanolone glucuronide, OCT with neurotransmitters, and OCTN/OCTN-related with ergothioneine and carnitine derivatives. Our data suggest that the SLC22 family can work among itself, as well as with other ADME genes, to optimize levels of numerous metabolites and signaling molecules, involved in organ crosstalk and inter-organismal communication, as proposed by the remote sensing and signaling theory.
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Arruda, Adriano Cleis, Mauro Sérgio Perilhão, Warley Almeida Santos, Marcos Fernandes Gregnani, Alexandre Budu, José Cesar Rosa Neto, Gabriel Rufino Estrela, and Ronaldo Carvalho Araujo. "PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice." Molecules 25, no. 2 (January 17, 2020): 392. http://dx.doi.org/10.3390/molecules25020392.
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Metformin is the first-line drug for type 2 diabetes mellitus control. It is established that this drug traffics through OCT-2 and MATE-1 transporters in kidney tubular cells and is excreted in its unaltered form in the urine. Hereby, we provide evidence that points towards the metformin-dependent upregulation of OCT-2 and MATE-1 in the kidney via the transcription factor proliferator-activated receptor alpha (PPARα). Treatment of wild type mice with metformin led to the upregulation of the expression of OCT-2 and MATE-1 by 34% and 157%, respectively. An analysis in a kidney tubular cell line revealed that metformin upregulated PPARα and OCT-2 expression by 37% and 299% respectively. MK-886, a PPARα antagonist, abrogated the OCT-2 upregulation by metformin and reduced MATE-1 expression. Conversely, gemfibrozil, an agonist of PPARα, elicited the increase of PPARα, OCT-2, and MATE-1 expression by 115%, 144%, and 376%, respectively. PPARα knockout mice failed to upregulate both the expression of OCT-2 and MATE-1 in the kidney upon metformin treatment, supporting the PPARα-dependent metformin upregulation of the transporters in this organ. Taken together, our data sheds light on the metformin-induced mechanism of transporter modulation in the kidney, via PPARα, and this effect may have implications for drug safety and efficacy.
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Labussière, Hélène, Sandrine Hayette, Kaddour Chabane, Marie-Claude Gagnieu, Quoc-Hung Lê, Isabelle Tigaud, Joëlle Bernard, et al. "Pharmacogenomic Factors Such as the Expression of Imatinib Transporters (OCT-1, ABCB-1 and ABCG-2) at Diagnosis, OCT-1 SNPs, and Steady-State Imatinib and Desmethyl-Imatinib Trough Plasma Levels in De Novo Chronic Phase Chronic Myelogenous Leukemia, May Influence Disease Response to Imatinib." Blood 112, no. 11 (November 16, 2008): 2643. http://dx.doi.org/10.1182/blood.v112.11.2643.2643.
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Abstract The treatment of chronic myelogenous leukemia (CML) with imatinib mesylate (IM) has dramatically improved the prognosis of this disease, notably for chronic phase (CP) patients. However, a significant proportion of CP patients may progress along the years and it is important to identify early markers of poor response in order to offer to such patients the best alternative treatment. It has been demonstrated recently that the activity of some membrane transporters such as the organic cation transporter 1 (OCT-1), and ATP-binding cassette transporters (ABCB-1 and ABCG-2) may modify IM intracellular concentrations within leukemic cells and influence disease response and survival. In this study, we enrolled 76 CP CML patients (47M, 29F) at diagnosis and we measured in 66 patients on peripheral blood (PB) samples with RQ-PCR, the levels of OCT-1, ABCB-1 and ABCG-2 and analyse the impact on disease response and steady-state plasmatic IM and desmethyl-IM trough concentrations. The transporter data generated were normalised using a pool of peripheral blood samples from 10 healthy blood donors. Additionally, OCT-1 SNPs in exons 1 to 9 have been analysed in 41 patients out of 76. Median age at diagnosis was 50.3 (18.1–81.8) years, Sokal score was high for 16 (21%), intermediate for 34 (45%) and low for 23 (30%) patients and unknown for 3 (4%), Hasford score was high for 5 (7%), intermediate for 29 (38%), low for 30 (39%), and unknown 12 (16%). IM alone was initiated at 400 mg/day for 50 patients, 600 mg/day for 3 patients, IM was associated to monthly subcutaneous courses of 14 days Cytarabine in 13 patients and to Peg-IFN-a in 10 patients the first year of treatment. Heighty eight percent of patients were in optimal cytogenetic response (PCyR) at 6 months. Seven percent, 33%, 39%, 46%, 59% and 63% of patients were in major molecular response [MMR, BCR-ABL/ABL (IS) <0.1%] at 3, 6, 9, 12, 18 and 24 months respectively. Univariate analysis demonstrated a significant correlation (p=0.04) between ABCG-2 RQ-PCR levels at diagnosis and the proportion of patients in MMR at 6 months, between ABCB-1 levels and MMR at 12 months (p<0.01), and between OCT-1 levels and MMR at 24 months. A conditional logistic-regression model was used to analyse associations between molecular responses and transporter RQ-PCR levels, age, gender, Sokal and Hasford scores, and showed that only ABCB-1 levels were a favourable factor on the MMR rate at 12 months (HR= 2.62, 95%CI= 2.32–6.10). Logrank test did not find any significant impact of transporters levels, IM and desmethyl-IM trough concentrations, on disease progression. More extensive statistical analysis will be presented. OCT-1 SNPs analysis identified 3 patients with polymporphisms reported to decrease the enzymatic activity of OCT-1 (exon 1) and 1 patient with a polymorphism reported to fully abolish OCT-1 activity (exon 1). However, these 4 patients showed optimal cytogenetic and molecular responses, suggesting the involvement of other mechanisms in the regulation of the response to IM. Ten patients were identified with OCT-1 polymorphisms (in exons 2, 3 and 7) reported not to influence the enzymatic activity of this protein. In conclusion, the activity of these transporters (as assessed by RQ-PCR) may have some impact on the molecular response of CP CML to front-line IM therapy, however, the interrelationships between the different transporters in conjunction with other factors (drug-drug interactions, genetic background…) do not contribute to clearly distinguish one transporter more than another as a key prognostic factor for IM-molecular disease control.
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Nies, Anne T., Jörg König, Ute Hofmann, Charlotte Kölz, Martin F. Fromm, and Matthias Schwab. "Interaction of Remdesivir with Clinically Relevant Hepatic Drug Uptake Transporters." Pharmaceutics 13, no. 3 (March 10, 2021): 369. http://dx.doi.org/10.3390/pharmaceutics13030369.
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Remdesivir has been approved for treatment of COVID-19 and shortens the time to recovery in hospitalized patients. Drug transporters removing remdesivir from the circulation may reduce efficacy of treatment by lowering its plasma levels. Information on the interaction of remdesivir with drug transporters is limited. We therefore assessed remdesivir as substrate and inhibitor of the clinically relevant hepatic drug uptake transporters organic anion transporting poly-peptide (OATP)-1B1 (SLCO1B1), its common genetic variants OATP1B1*1b, OATP1B1*5, OATP1B1*15, as well as OATP1B3 (SLCO1B3), OATP2B1 (SLCO2B1) and organic cation transporter (OCT)-1 (SLC22A1). Previously established transporter-overexpressing cells were used to measure (i) cellular remdesivir uptake and (ii) cellular uptake of transporter probe substrates in the presence of remdesivir. There was a high remdesivir uptake into vector-transfected control cells. Moderate, but statistically significant higher uptake was detected only for OATP1B1-, OATP1B1*1b and OATP1B1*15-expressing cells when compared with control cells at 5 µM. Remdesivir inhibited all investigated transporters at 10 µM and above. In conclusion, the low uptake rates suggest that OATP1B1 and its genetic variants, OATP1B3, OATP2B1 and OCT1 are not relevant for hepatocellular uptake of remdesivir in humans. Due to the rapid clearance of remdesivir, no clinically relevant transporter-mediated drug-drug interactions are expected.
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Sweet, Douglas H., Kevin T. Bush, and Sanjay K. Nigam. "The organic anion transporter family: from physiology to ontogeny and the clinic." American Journal of Physiology-Renal Physiology 281, no. 2 (August 1, 2001): F197—F205. http://dx.doi.org/10.1152/ajprenal.2001.281.2.f197.
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The organic anion transporter (OAT) family handles a wide variety of clinically important compounds (antibiotics, nonsteriodal anti-inflammatory drugs, etc.) and toxins. However, little is known about their appearance during development despite documented differences in the handling of anionic drugs among neonates, children, and adults. A similar spatiotemporal pattern of mRNA expression of the OATs (OAT1–4) during kidney development suggests that OAT genes may be useful in understanding the mechanisms of proximal tubule maturation. Moreover, OAT expression in unexpected extrarenal sites (e.g., spinal cord, bone, skin) has also been detected during development, possibly indicating a role for these transporters in the formation or preservation of extrarenal tissues. The cloning of these transporters also paves the way for computer-based modeling of drug-transporter interactions at the molecular level, potentially aiding in the design and assessment of new drugs. Additionally, increased understanding of single nucleotide polymorphisms in OATs and other transporters may eventually allow the use of a patient's expression profile and polymorphisms to individualize drug therapy.
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Gaiko, Olga, Ingo Janausch, Sven Geibel, Henning Vollert, Petra Arndt, Sigrid Gonski, and Klaus Fendler. "Robust Electrophysiological Assays using Solid Supported Membranes: the Organic Cation Transporter OCT2." Australian Journal of Chemistry 64, no. 1 (2011): 31. http://dx.doi.org/10.1071/ch10322.
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An electrophysiological assay platform based on solid supported membranes (SSM) for the organic cation transporter (OCT) is presented. Stable Chinese hamster ovary (CHO) cell lines overexpressing the human (hOCT2) and rat transporters (rOCT2) were generated and validated. Membrane preparations from the cell lines were investigated using SSM-based electrophysiology. Baculovirus transfected insect cells (HighFive and Mimic Sf9) were also tested with the same assay but yielded less than optimal results. The assays were validated by the determination of substrate affinities and inhibition by standard inhibitors. The study demonstrates the suitability of the SSM-based electrophysiological OCT assay for rapid and automatic screening of drug candidates.
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Shitara, Yoshihisa, Hitoshi Sato, and Yuichi Sugiyama. "EVALUATION OF DRUG-DRUG INTERACTION IN THE HEPATOBILIARY AND RENAL TRANSPORT OF DRUGS." Annual Review of Pharmacology and Toxicology 45, no. 1 (September 22, 2005): 689–723. http://dx.doi.org/10.1146/annurev.pharmtox.44.101802.121444.
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Recent studies have revealed the import role played by transporters in the renal and hepatobiliary excretion of many drugs. These transporters exhibit a broad substrate specificity with a degree of overlap, suggesting the possibility of transporter-mediated drug-drug interactions with other substrates. This review is an overview of the roles of transporters and the possibility of transporter-mediated drug-drug interactions. Among the large number of transporters, we compare the Ki values of inhibitors for organic anion transporting polypeptides (OATPs) and organic anion transporters (OATs) and their therapeutic unbound concentrations. Among them, cephalosporins and probenecid have the potential to produce clinically relevant OAT-mediated drug-drug interactions, whereas cyclosporin A and rifampicin may trigger OATP-mediated ones. These drugs have been reported to cause drug-drug interactions in vivo with OATs or OATP substrates, suggesting the possibility of transporter-mediated drug-drug interactions. To avoid adverse consequences of such transporter-mediated drug-drug interactions, we need to be more aware of the role played by drug transporters as well as those caused by drug metabolizing enzymes.
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Zhang, Xiaohong, Carlotta E. Groves, Andrew Bahn, Wendy M. Barendt, Marcos D. Prado, Matthias Rödiger, Varanuj Chatsudthipong, Gerhard Burckhardt, and Stephen H. Wright. "Relative contribution of OAT and OCT transporters to organic electrolyte transport in rabbit proximal tubule." American Journal of Physiology-Renal Physiology 287, no. 5 (November 2004): F999—F1010. http://dx.doi.org/10.1152/ajprenal.00156.2004.
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We compared the characteristics of several cloned rabbit organic electrolyte (OE) transporters expressed in cultured cells with their behavior in intact rabbit renal proximal tubules (RPT) to determine the contribution of each to basolateral uptake of the weak acid ochratoxin A (OTA) and the weak base cimetidine (CIM). The activity of organic anion transporters OAT1 and OAT3 proved to be distinguishable because OAT1 had a high affinity for PAH ( Ktof 20 μM) and did not support estrone sulfate (ES) transport, whereas OAT3 had a high affinity for ES ( Ktof 4.5 μM) and a weak interaction with PAH (IC50> 1 mM). In contrast, both transporters robustly accumulated OTA. Intact RPT also accumulated OTA, with OAT1 and OAT3 each responsible for ∼50%: ES and PAH each reduced uptake by ∼50%, and the combination of the two eliminated mediated OTA uptake. The weak base CIM was transported by OAT3 ( Ktof 80 μM) and OCT2 ( Ktof 2 μM); OCT1 had a comparatively low affinity for CIM, and CIM uptake by OAT1 was equivocal. Intact RPT accumulated CIM, with TEA and ES reducing CIM uptake by 20 and 75%, respectively, suggesting that OAT3 plays a quantitatively more significant role in CIM uptake in the early proximal tubule than OCT1/2. In single S2 segments of RPT, ES and TEA each blocked ∼50% of CIM uptake. Thus the fractional contribution of different OE transporters to renal secretion is influenced by their affinity for substrate and relative expression level in RPT.
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Eraly, Satish A., Julio C. Monte, and Sanjay K. Nigam. "Novel slc22 transporter homologs in fly, worm, and human clarify the phylogeny of organic anion and cation transporters." Physiological Genomics 18, no. 1 (June 17, 2004): 12–24. http://dx.doi.org/10.1152/physiolgenomics.00014.2004.
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Slc22 family organic anion and cation transporters (OATs, OCTs, and OCTNs) are transmembrane proteins expressed predominantly in kidney and liver. These proteins mediate the uptake or excretion of numerous physiologically (and pharmacologically) important compounds, and accordingly have been the focus of intensive study. Here we investigate the molecular phylogeny of the slc22 transporters, identifying homologs in Drosophila and C. elegans, several of which are developmentally regulated, as well as reporting the cloning of a novel human family member, UST6, expressed exclusively in liver in both embryo and adult. The latter helps define a subfamily within the OATs, which appears to have human- and rodent-specific members, raising potential issues with respect to the use of rodents as models for the transport of organic anions (which include many pharmaceuticals) in humans. Although this phylogenetic inference could not be made on the basis of sequence alignment, analysis of intron phasing suggests that the OAT, OCT, and OCTN lineages of the slc22 family formed after the divergence of vertebrates and invertebrates. Subsequently, these lineages expanded through independent tandem duplications to produce multiple gene pairs. After analyzing over 200 other transporter genes, we find such pairing to be relatively specific to vertebrate organic anion and cation transporters, suggesting selection for gene pairing operating within this family in particular. This might reflect a requirement for redundancy or broader substrate specificity in vertebrates (compared to invertebrates), due to their greater physiological complexity and thus potentially broader exposure to organic ions.
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Karbach, Ulrich, Jörn Kricke, Friederike Meyer-Wentrup, Valentin Gorboulev, Christopher Volk, Dominique Loffing-Cueni, Brigitte Kaissling, Sebastian Bachmann, and Hermann Koepsell. "Localization of organic cation transporters OCT1 and OCT2 in rat kidney." American Journal of Physiology-Renal Physiology 279, no. 4 (October 1, 2000): F679—F687. http://dx.doi.org/10.1152/ajprenal.2000.279.4.f679.
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Renal excretion and reabsorption of organic cations are mediated by electrogenic and electroneutral organic cation transporters, which belong to a recently discovered family of polyspecific transporters. These transporters are electrogenic and exhibit differences in substrate specificity. In rat, the renal expression of the polyspecific cation transporters rOCT1 and rOCT2 was investigated. By in situ hybridization, significant amounts of both rOCT1 and rOCT2 mRNA were detected in S1, S2, and S3 segments of proximal tubules. By immunohistochemistry, expression of the rOCT1 protein was mainly observed in S1 and S2 segments of proximal tubules, with lower expression levels in the S3 segments. At variance, rOCT2 protein was mainly expressed in the S2 and S3 segments. Both transporters were localized to the basolateral cell membrane. Neither rOCT1 nor rOCT2 was detected in the vasculature, the glomeruli, and nephron segments other than proximal tubules. The data suggest that rOCT1 and rOCT2 are responsible for basolateral cation uptake in the proximal tubule, which represents the first step in cation secretion.
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Horvath, Gabor, Zoltan Sutto, Aliza Torbati, Gregory E. Conner, Matthias Salathe, and Adam Wanner. "Norepinephrine transport by the extraneuronal monoamine transporter in human bronchial arterial smooth muscle cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 285, no. 4 (October 2003): L829—L837. http://dx.doi.org/10.1152/ajplung.00054.2003.
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Inhaled glucocorticosteroids (GSs) cause acute, α1-adrenoreceptor (AR)-mediated bronchial vasoconstriction. After release from sympathetic nerves, norepinephrine (NE) must be taken up into cells for deactivation by intracellular enzymes. Because postsynaptic cellular NE uptake is steroid sensitive, GSs could increase NE concentrations at α1-AR, causing vasoconstriction. We therefore evaluated mRNA expression of different NE transporters in human bronchial arterial smooth muscle and pharmacologically characterized NE uptake into these cells. RT-PCR demonstrated mRNA expression of the extraneuronal monoamine transporter (EMT) and organic cation transporter 1 (OCT-1). Fluorometric uptake assay showed time (within minutes)- and concentration-dependent NE uptake by freshly isolated bronchial arterial smooth muscle cells (SMC) with an estimated Km of 240 μM. Corticosterone and O-methylisoprenaline (1 μM each), but not desipramine, inhibited NE uptake, a profile indicative of NE uptake by EMT, but not OCT-1. Budesonide and methylprednisolone inhibited uptake with IC50 values of 0.9 and 5.6 μM, respectively. Corticosterone's action was reversible and not sensitive to RU-486 (GS receptor antagonist), actinomycin D (transcription inhibitor), or cycloheximide (protein synthesis inhibitor). Corticosterone made membrane impermeant by coupling to BSA also blocked NE uptake. Immunocytochemistry indicated a specific membrane binding site for corticosterone on bronchial arterial SMC. These data demonstrate that although human bronchial arterial SMC express OCT-1 and EMT, EMT is the predominant plasma membrane transporter for NE uptake. This process can be inhibited by GSs, likely via a specific membrane binding site. This nongenomic GS action (increasing NE concentrations at α1-AR) could explain acute bronchial vasoconstriction caused by inhaled GSs.
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Kim, Sunjoo, Dong Kyun Kim, Yongho Shin, Ji-Hyeon Jeon, Im-Sook Song, and Hye Suk Lee. "In Vitro Interaction of AB-FUBINACA with Human Cytochrome P450, UDP-Glucuronosyltransferase Enzymes and Drug Transporters." Molecules 25, no. 19 (October 8, 2020): 4589. http://dx.doi.org/10.3390/molecules25194589.
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AB-FUBINACA, a synthetic indazole carboxamide cannabinoid, has been used worldwide as a new psychoactive substance. Because drug abusers take various drugs concomitantly, it is necessary to explore potential AB-FUBINACA-induced drug–drug interactions caused by modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of AB-FUBINACA on eight major human cytochrome P450s (CYPs) and six uridine 5′-diphospho-glucuronosyltransferases (UGTs) of human liver microsomes, and on eight clinically important transport activities including organic cation transporters (OCT)1 and OCT2, organic anion transporters (OAT)1 and OAT3, organic anion transporting polypeptide transporters (OATP)1B1 and OATP1B3, P-glycoprotein, and breast cancer resistance protein (BCRP) in transporter-overexpressing cells were investigated. AB-FUBINACA inhibited CYP2B6-mediated bupropion hydroxylation via mixed inhibition with Ki value of 15.0 µM and competitively inhibited CYP2C8-catalyzed amodiaquine N-de-ethylation, CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP2C19-catalyzed [S]-mephenytoin 4′-hydroxylation, and CYP2D6-catalyzed bufuralol 1′-hydroxylation with Ki values of 19.9, 13.1, 6.3, and 20.8 µM, respectively. AB-FUBINACA inhibited OCT2-mediated MPP+ uptake via mixed inhibition (Ki, 54.2 µM) and competitively inhibited OATP1B1-mediated estrone-3-sulfate uptake (Ki, 94.4 µM). However, AB-FUBINACA did not significantly inhibit CYP1A2, CYP2A6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, or UGT2B7 enzyme activities at concentrations up to 100 µM. AB-FUBINACA did not significantly inhibit the transport activities of OCT1, OAT1/3, OATP1B3, P-glycoprotein, or BCRP at concentrations up to 250 μM. As the pharmacokinetics of AB-FUBINACA in humans and animals remain unknown, it is necessary to clinically evaluate potential in vivo pharmacokinetic drug–drug interactions induced by AB-FUBINACA-mediated inhibition of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, OCT2, and OATP1B1 activities.
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Gu, Yi-Zhong, Xiaoyan Chu, Robert Houle, Katerina Vlasakova, Kenneth A. Koeplinger, Isabelle Bourgeois, Kiran Palyada, et al. "Polyethlyene Glycol 200 Can Protect Rats Against Drug-Induced Kidney Toxicity Through Inhibition of the Renal Organic Anion Transporter 3." Toxicological Sciences 172, no. 1 (August 12, 2019): 155–66. http://dx.doi.org/10.1093/toxsci/kfz186.
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Abstract MK-7680, a cyclic nucleotide prodrug, caused significant kidney tubule injury in female rats when administered orally at 1000 mg/kg/day for 2 weeks using 10% Polysorbate 80 as vehicle. However, kidney injury was absent when MK-7680 was administered at the same dose regimen using 100% Polyethylene Glycol 200 (PEG 200) as the vehicle. Subsequent investigations revealed that MK-7680 triphosphate concentrations in kidney were much lower in rats treated with MK-7680 using PEG 200 compared with 10% Polysorbate 80 vehicle, whereas plasma exposures of MK-7680 prodrug were similar. In vitro studies demonstrated that PEG 200 is an inhibitor of human renal uptake transporter organic anion transporter 3 (OAT3), of which MK-7680 is a substrate. Furthermore, PEG 200 and PEG 400 were found to interfere in vitro with human renal transporters OAT3, organic cation transporter (OCT) 2, multidrug resistance-associated protein (MRP) 2 and 4, and multidrug and toxin extrusion protein (MATE) 1 and 2K, but not OAT1. These results support a conclusion that PEG 200 may prevent MK-7680-induced kidney injury by inhibiting its active uptake into proximal tubular cells by OAT3. Caution should be exercised therefore when using PEGs as vehicles for toxicity assessment for compounds that are substrates of renal transporters.
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Selo, Mohammed Ali, Johannes A. Sake, Carsten Ehrhardt, and Johanna J. Salomon. "Organic Cation Transporters in the Lung—Current and Emerging (Patho)Physiological and Pharmacological Concepts." International Journal of Molecular Sciences 21, no. 23 (December 1, 2020): 9168. http://dx.doi.org/10.3390/ijms21239168.
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Organic cation transporters (OCT) 1, 2 and 3 and novel organic cation transporters (OCTN) 1 and 2 of the solute carrier 22 (SLC22) family are involved in the cellular transport of endogenous compounds such as neurotransmitters, l-carnitine and ergothioneine. OCT/Ns have also been implicated in the transport of xenobiotics across various biological barriers, for example biguanides and histamine receptor antagonists. In addition, several drugs used in the treatment of respiratory disorders are cations at physiological pH and potential substrates of OCT/Ns. OCT/Ns may also be associated with the development of chronic lung diseases such as allergic asthma and chronic obstructive pulmonary disease (COPD) and, thus, are possible new drug targets. As part of the Special Issue “Physiology, Biochemistry and Pharmacology of Transporters for Organic Cations”, this review provides an overview of recent findings on the (patho)physiological and pharmacological functions of organic cation transporters in the lung.
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Zazuli, Zulfan, Naut J. C. B. Duin, Katja Jansen, Susanne J. H. Vijverberg, Anke H. Maitland-van der Zee, and Rosalinde Masereeuw. "The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition." International Journal of Molecular Sciences 21, no. 18 (September 10, 2020): 6627. http://dx.doi.org/10.3390/ijms21186627.
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A considerable number of drugs and/or their metabolites are excreted by the kidneys through glomerular filtration and active renal tubule secretion via transporter proteins. Uptake transporters in the proximal tubule are part of the solute carrier (SLC) superfamily, and include the organic cation transporters (OCTs). Several studies have shown that specific genetic polymorphisms in OCTs alter drug disposition and may lead to nephrotoxicity. Multiple single nucleotide polymorphisms (SNPs) have been reported for the OCT genes (SLC22A1, SLC22A2 and SLC22A3), which can influence the proteins’ structure and expression levels and affect their transport function. A gain-in-function mutation may lead to accumulation of drugs in renal proximal tubule cells, eventually leading to nephrotoxicity. This review illustrates the impact of genetic polymorphisms in OCTs on renal drug disposition and kidney injury, the clinical significances and how to personalize therapies to minimize the risk of drug toxicity.
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Sekine, Takashi, Hiroki Miyazaki, and Hitoshi Endou. "Molecular physiology of renal organic anion transporters." American Journal of Physiology-Renal Physiology 290, no. 2 (February 2006): F251—F261. http://dx.doi.org/10.1152/ajprenal.00439.2004.
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Recent advances in molecular biology have identified three organic anion transporter families: the organic anion transporter (OAT) family encoded by SLC22A, the organic anion transporting peptide (OATP) family encoded by SLC21A ( SLCO), and the multidrug resistance-associated protein (MRP) family encoded by ABCC. These families play critical roles in the transepithelial transport of organic anions in the kidneys as well as in other tissues such as the liver and brain. Among these families, the OAT family plays the central role in renal organic anion transport. Knowledge of these three families at the molecular level, such as substrate selectivity, tissue distribution, and gene localization, is rapidly increasing. In this review, we will give an overview of molecular information on renal organic anion transporters and describe recent topics such as the regulatory mechanisms and molecular physiology of urate transport. We will also discuss the physiological roles of each organic anion transporter in the light of the transepithelial transport of organic anions in the kidneys.
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Wright, Stephen H. "Molecular and cellular physiology of organic cation transporter 2." American Journal of Physiology-Renal Physiology 317, no. 6 (December 1, 2019): F1669—F1679. http://dx.doi.org/10.1152/ajprenal.00422.2019.
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Organic cation transporters play a critical role in mediating the distribution of cationic pharmaceuticals. Indeed, organic cation transporter (OCT)2 is the initial step in the renal secretion of organic cations and consequently plays a defining role in establishing the pharmacokinetics of many cationic drugs. Although a hallmark of OCTs is their broad selectivity, this characteristic also makes them targets for unwanted, adverse drug-drug interactions (DDIs), making them a focus for efforts to develop models of ligand interaction that could predict and preempt these adverse interactions. This review discusses the molecular characteristics of these transporters as well as the evidence that established the OCTs as key players in the distribution of organic cations. However, the primary focus is the present understanding of the complexity of ligand interaction with OCTs, particularly OCT2, including evidence for the presence of multiple ligand-binding sites and the influence of substrate structure on the affinity of the transporter for inhibitory ligands. This leads to a discussion of the complexities associated with the development of protocols for assessing the inhibitory potential of new molecular entities to perpetrate unwanted DDIs, the criteria that should be considered in the interpretation of the results of such protocols, and the challenges associated with development of models capable of predicting unwanted DDIs.
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Miakotina, Olga L., Marianna Agassandian, Lei Shi, Dwight C. Look, and Rama K. Mallampalli. "Adenovirus stimulates choline efflux by increasing expression of organic cation transporter-2." American Journal of Physiology-Lung Cellular and Molecular Physiology 288, no. 1 (January 2005): L93—L102. http://dx.doi.org/10.1152/ajplung.00184.2004.
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We examined the effect of wild-type human adenovirus (Ad5) on choline transport in murine lung epithelia (MLE) and in rodent primary alveolar type II cells. Cells were active in pH-sensitive, reversible transport of choline, a process blocked pharmacologically with phenoxybenzamine, an inhibitor of organic cation transporters (OCT). PCR products for the choline transporters, OCT-1 and OCT-2, were detected, but only OCT-2 protein was robustly expressed within MLE and primary alveolar epithelial cells. Ad5 produced a two- to threefold increase in choline efflux from cells, resulting in a significant reduction in intracellular choline content and its major product, phosphatidylcholine. Effects of Ad5 on choline efflux were inhibited with phenoxybenzamine, and choline efflux was attenuated by OCT-2 small interfering RNA. Adenovirus also produced a dose-dependent increase in immunoreactive OCT-2 levels concomitant with increased cellular OCT-2 steady-state mRNA. These results indicate that adenoviruses can significantly disrupt choline trafficking in lung epithelia by upregulating expression of an alveolar protein involved in organic cation transport.
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Tzvetkov, M. V., S. V. Vormfelde, D. Balen, I. Meineke, T. Schmidt, D. Sehrt, I. Sabolić, H. Koepsell, and J. Brockmöller. "The Effects of Genetic Polymorphisms in the Organic Cation Transporters OCT1, OCT2, and OCT3 on the Renal Clearance of Metformin." Clinical Pharmacology & Therapeutics 86, no. 3 (June 17, 2009): 299–306. http://dx.doi.org/10.1038/clpt.2009.92.
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Pavlova, Anna, Hiroyuki Sakurai, Baudouin Leclercq, David R. Beier, Alan S. L. Yu, and Sanjay K. Nigam. "Developmentally regulated expression of organic ion transporters NKT (OAT1), OCT1, NLT (OAT2), and Roct." American Journal of Physiology-Renal Physiology 278, no. 4 (April 1, 2000): F635—F643. http://dx.doi.org/10.1152/ajprenal.2000.278.4.f635.
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Several xenobiotic (organic cation and anion) transporters have recently been identified, although their endogenous substrates, if such exist, remain unknown. When we initially identified NKT, also known as OAT1, the first member of the organic anion transporter (OAT) family (Lopez-Nieto CE, You G, Bush KT, Barros EJ, Beier DR, and Nigam SK. J Biol Chem 272: 6471–6478, 1997), we noted its expression in the embryonic kidney. We have now demonstrated its transporter function and more fully examined the spatiotemporal expression patterns of representative organic ion transporters, [NKT (OAT1), Roct, OCT1, and NLT, also known as OAT2] during murine development. In the kidney, NKT (OAT1), OCT1, and Roct transcripts appeared at midgestation, coinciding with proximal tubule differentiation, and gradually increased during nephron maturation. A similar pattern was observed for NLT (OAT2) in the liver and kidney, although, in the kidney, NLT (OAT2) transcription did not increase as dramatically. The roughly cotemporal expression of these related transporters in the developing proximal tubule may indicate common transcriptional regulation. Expression during embryogenesis in extrarenal sites could suggest a role in the formation and maintenance of nonrenal tissues. Importantly, all four genes were expressed in unexpected places during nonrenal organogenesis: Roct in the fetal liver (temporally coinciding with the onset of hematopoiesis) and neural tissue; NKT (OAT1) in the fetal brain; OCT1 in the ascending aorta and atrium; and NLT (OAT2) in the fetal lung, intestine, skin, and developing bone. Because these gene products mediate the transport of a broad range of metabolites and toxins, it seems likely that, apart from their known functions, these transporters play a role in transport of organic molecules, perhaps including those with morphogenetic activity. These genes could also play important developmental roles independent of transport function.
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Kang, Yun Ju, Chul Haeng Lee, Soo-Jin Park, Hye Suk Lee, Min-Koo Choi, and Im-Sook Song. "Involvement of Organic Anion Transporters in the Pharmacokinetics and Drug Interaction of Rosmarinic Acid." Pharmaceutics 13, no. 1 (January 9, 2021): 83. http://dx.doi.org/10.3390/pharmaceutics13010083.
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We investigated the involvement of drug transporters in the pharmacokinetics of rosmarinic acid in rats as well as the transporter-mediated drug interaction potential of rosmarinic acid in HEK293 cells overexpressing clinically important solute carrier transporters and also in rats. Intravenously injected rosmarinic acid showed bi-exponential decay and unchanged rosmarinic acid was mainly eliminated by urinary excretion, suggesting the involvement of transporters in its renal excretion. Rosmarinic acid showed organic anion transporter (OAT)1-mediated active transport with a Km of 26.5 μM and a Vmax of 69.0 pmol/min in HEK293 cells overexpressing OAT1, and the plasma concentrations of rosmarinic acid were increased by the co-injection of probenecid because of decreased renal excretion due to OAT1 inhibition. Rosmarinic acid inhibited the transport activities of OAT1, OAT3, organic anion transporting polypeptide (OATP)1B1, and OATP1B3 with IC50 values of 60.6 μM, 1.52 μM, 74.8 μM, and 91.3 μM, respectively, and the inhibitory effect of rosmarinic acid on OAT3 transport activity caused an in vivo pharmacokinetic interaction with furosemide by inhibiting its renal excretion and by increasing its plasma concentration. In conclusion, OAT1 and OAT3 are the major transporters that may regulate the pharmacokinetic properties of rosmarinic acid and may cause herb-drug interactions with rosmarinic acid, although their clinical relevance awaits further evaluation.
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Kang, Yun Ju, Chul Haeng Lee, Soo-Jin Park, Hye Suk Lee, Min-Koo Choi, and Im-Sook Song. "Involvement of Organic Anion Transporters in the Pharmacokinetics and Drug Interaction of Rosmarinic Acid." Pharmaceutics 13, no. 1 (January 9, 2021): 83. http://dx.doi.org/10.3390/pharmaceutics13010083.
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We investigated the involvement of drug transporters in the pharmacokinetics of rosmarinic acid in rats as well as the transporter-mediated drug interaction potential of rosmarinic acid in HEK293 cells overexpressing clinically important solute carrier transporters and also in rats. Intravenously injected rosmarinic acid showed bi-exponential decay and unchanged rosmarinic acid was mainly eliminated by urinary excretion, suggesting the involvement of transporters in its renal excretion. Rosmarinic acid showed organic anion transporter (OAT)1-mediated active transport with a Km of 26.5 μM and a Vmax of 69.0 pmol/min in HEK293 cells overexpressing OAT1, and the plasma concentrations of rosmarinic acid were increased by the co-injection of probenecid because of decreased renal excretion due to OAT1 inhibition. Rosmarinic acid inhibited the transport activities of OAT1, OAT3, organic anion transporting polypeptide (OATP)1B1, and OATP1B3 with IC50 values of 60.6 μM, 1.52 μM, 74.8 μM, and 91.3 μM, respectively, and the inhibitory effect of rosmarinic acid on OAT3 transport activity caused an in vivo pharmacokinetic interaction with furosemide by inhibiting its renal excretion and by increasing its plasma concentration. In conclusion, OAT1 and OAT3 are the major transporters that may regulate the pharmacokinetic properties of rosmarinic acid and may cause herb-drug interactions with rosmarinic acid, although their clinical relevance awaits further evaluation.
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Song, Im-Sook. "Pharmacogenomics and metabolomics approaches of OCT transporters." Drug Metabolism and Pharmacokinetics 32, no. 1 (January 2017): S9. http://dx.doi.org/10.1016/j.dmpk.2016.10.048.
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Aslamkhan, Amy G., Deborah M. Thompson, Jennifer L. Perry, Kelly Bleasby, Natascha A. Wolff, Scott Barros, David S. Miller, and John B. Pritchard. "The flounder organic anion transporter fOat has sequence, function, and substrate specificity similarity to both mammalian Oat1 and Oat3." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 6 (December 2006): R1773—R1780. http://dx.doi.org/10.1152/ajpregu.00326.2006.
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The flounder renal organic anion transporter (fOat) has substantial sequence homology to mammalian basolateral organic anion transporter orthologs (OAT1/Oat1 and OAT3/Oat3), suggesting that fOat may have functional properties of both mammalian forms. We therefore compared uptake of various substrates by rat Oat1 and Oat3 and human OAT1 and OAT3 with the fOat clone expressed in Xenopus oocytes. These data confirm that estrone sulfate is an excellent substrate for mammalian OAT3/Oat3 transporters but not for OAT1/Oat1 transporters. In contrast, 2,4-dichlorophenoxyacetic acid and adefovir are better transported by mammalian OAT1/Oat1 than by the OAT3/Oat3 clones. All three substrates were well transported by fOat-expressing Xenopus oocytes. fOat Km values were comparable to those obtained for mammalian OAT/Oat1/3 clones. We also characterized the ability of these substrates to inhibit uptake of the fluorescent substrate fluorescein in intact teleost proximal tubules isolated from the winter flounder ( Pseudopleuronectes americanus) and killifish ( Fundulus heteroclitus). The rank order of the IC50 values for inhibition of cellular fluorescein accumulation was similar to that for the Km values obtained in fOat-expressing oocytes, suggesting that fOat may be the primary teleost renal basolateral Oat. Assessment of the zebrafish ( Danio rerio) genome indicated the presence of a single Oat (zfOat) with similarity to both mammalian OAT1/Oat1 and OAT3/Oat3. The puffer fish ( Takifugu rubripes) also has an Oat (pfOat) similar to mammalian OAT1/Oat1 and OAT3/Oat3 members. Furthermore, phylogenetic analyses argue that the teleost Oat1/3-like genes diverged from a common ancestral gene in advance of the divergence of the mammalian OAT1/Oat1, OAT3/Oat3, and, possibly, Oat6 genes.
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Parvez, M. Masud, Nazia Kaisar, Ho Jung Shin, Jin Ah Jung, and Jae-Gook Shin. "Inhibitory Interaction Potential of 22 Antituberculosis Drugs on Organic Anion and Cation Transporters of the SLC22A Family." Antimicrobial Agents and Chemotherapy 60, no. 11 (August 22, 2016): 6558–67. http://dx.doi.org/10.1128/aac.01151-16.
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ABSTRACTTwenty-two currently marketed antituberculosis drugs were comprehensively evaluated for their inhibitory effect on organic anionic transporter (OAT)- and organic cation transporter (OCT)-mediated uptake using stably transfected HEK293 cellsin vitro. We observed moderate to strong inhibitory effects on OAT1- and OAT3-mediatedpara-aminohippurate (PAH) uptake and OCT1- and OCT2-mediatedN-methyl-4-phenylpylidinium acetate (MPP+) uptake. Ciprofloxacin, linezolid,para-aminosalicylic acid (PAS), and rifampin were observed to have strong inhibitory effects, with the concentrations for a 50% inhibitory effect (IC50s) being 35.1, 31.1, 37.6, and 48.1 μM, respectively, for OAT1 and >100, 21.9, 24.6, and 30.2 μM, respectively, for OAT3. Similarly, pyrazinamide, rifabutin, and levofloxacin were observed to have inhibitory effects, with IC50values being 36.5, 42.7, and 30.3 μM, respectively, for OCT1 and with the IC50value for PAS being 94.2 μM for OCT2. In addition, we used zidovudine and metformin as clinically prescribed substrates of OATs and OCTs, respectively, and zidovudine and metformin uptake was also strongly inhibited by the antituberculosis drugs. Among the tested drugs, the highest drug-drug interaction (DDI) indexes were found for PAS, which were 9.3 to 13.9 for OAT1 and 12.0 to 17.7 for OAT3, and linezolid, which were 1.18 to 2.15 for OAT1 and 1.7 to 3.01 for OAT3. Similarly, the DDI indexes of pyrazinamide and levofloxacin were 0.57 and 0.30, respectively, for OCT1, and the DDI index of PAS was 3.8 for OCT2, suggesting a stronger possibility (DDI index value cutoff, >0.1) ofin vivoDDIs. This is the first comprehensive report of the inhibitory potential of anti-TB drugs on OAT- and OCT-mediated uptake of prototype and clinically prescribed substrate drugsin vitro, providing an ability to predict DDIs between anti-TB drugs and other coprescribed drugs in clinical studiesin vivo.
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Yang, Hong, Shiwei Zhou, Dong Guo, Obinna N. Obianom, Qing Li, and Yan Shu. "Divergent Regulation of OCT and MATE Drug Transporters by Cadmium Exposure." Pharmaceutics 13, no. 4 (April 13, 2021): 537. http://dx.doi.org/10.3390/pharmaceutics13040537.
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Coordinated transcellular transport by the uptake via organic cation transporters (OCTs) in concert with the efflux via multidrug and toxin extrusion proteins (MATEs) is an essential system for hepatic and renal drug disposition. Despite their clinical importance, the regulation of OCTs and MATEs remains poorly characterized. It has been reported that cadmium (Cd2+) increase the activities of OCTs while being a substrate of MATEs. Here, we found that human (h) OCT2 protein, as compared with hMATE1, was more active in trafficking between the plasma membrane and cytoplasmic storage pool. Cd2+ exposure could significantly enhance the translocation of hOCT2 and hOCT1, but not hMATE1, to the plasma membrane. We further identified that candesartan, a widely prescribed angiotensin II receptor blocker, behaved similarly toward OCT2 and MATE1 as Cd2+ did. Importantly, Cd2+ and candesartan treatments could lead to an enhanced accumulation of metformin, which is a well-characterized substrate of OCTs/MATEs, in mouse kidney and liver, respectively. Altogether, our studies have uncovered possible divergent regulation of OCTs and MATEs by certain xenobiotics, such as Cd2+ and candesartan due to the different cellular trafficking of these two families of transporter proteins, which might significantly affect drug disposition in the liver and kidney.
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TSIGELNY, IGOR F., JERRY GREENBERG, VALENTINA KOUZNETSOVA, and SANJAY K. NIGAM. "MODELING OF GLYCEROL-3-PHOSPHATE TRANSPORTER SUGGESTS A POTENTIAL 'TILT' MECHANISM INVOLVED IN ITS FUNCTION." Journal of Bioinformatics and Computational Biology 06, no. 05 (October 2008): 885–904. http://dx.doi.org/10.1142/s0219720008003801.
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Many major facilitator superfamily (MFS) transporters have similar 12-transmembrane α-helical topologies with two six-helix halves connected by a long loop. In humans, these transporters participate in key physiological processes and are also, as in the case of members of the organic anion transporter (OAT) family, of pharmaceutical interest. Recently, crystal structures of two bacterial representatives of the MFS family — the glycerol-3-phosphate transporter (GlpT) and lac-permease (LacY) — have been solved and, because of assumptions regarding the high structural conservation of this family, there is hope that the results can be applied to mammalian transporters as well. Based on crystallography, it has been suggested that a major conformational "switching" mechanism accounts for ligand transport by MFS proteins. This conformational switch would then allow periodic changes in the overall transporter configuration, resulting in its cyclic opening to the periplasm or cytoplasm. Following this lead, we have modeled a possible "switch" mechanism in GlpT, using the concept of rotation of protein domains as in the DynDom program17and membranephilic constraints predicted by the MAPAS program.23We found that the minima of energies of intersubunit interactions support two alternate positions consistent with their transport properties. Thus, for GlpT, a "tilt" of 9°–10° rotation had the most favorable energetics of electrostatic interaction between the two halves of the transporter; moreover, this confirmation was sufficient to suggest transport of the ligand across the membrane. We conducted steered molecular dynamics simulations of the GlpT-ligand system to explore how glycerol-3-phosphate would be handled by the "tilted" structure, and obtained results generally consistent with experimental mutagenesis data. While biochemical data remain most consistent with a single-site alternating access model, our results raise the possibility that, while the "rocker switch" may apply to certain MFS transporters, intermediate "tilted" states may exist under certain circumstances or as transitional structures. Although wet lab experimental confirmation is required, our results suggest that transport mechanisms in this transporter family should probably not be assumed to be conserved simply based on standard structural homology considerations. Furthermore, steered molecular dynamics elucidating energetic interactions of ligands with amino acid residues in an appropriately modeled transporter may have predictive value in understanding the impact of mutations and/or polymorphisms on transporter function.
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Meyer zu Schwabedissen, Henriette E., Celine Verstuyft, Heyo K. Kroemer, Laurent Becquemont, and Richard B. Kim. "Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms." American Journal of Physiology-Renal Physiology 298, no. 4 (April 2010): F997—F1005. http://dx.doi.org/10.1152/ajprenal.00431.2009.
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renal elimination of a number of cationic compounds is thought to be mediated by the organic cation transporter 2 (OCT2, SLC22A2), a drug uptake transporter expressed at the basolateral domain of renal tubular cells. Recently, the key efflux transporter for the secretion organic cations was identified as an electroneutral H+/organic cation exchanger termed the multidrug and toxin extrusion (MATE)-type transporter 1 (MATE1, SLC47A1). The key goals of this study were to assess the interplay between the renal cationic transporters OCT2 and MATE1 and the functional assessment of genetic variation in human MATE1. First, the ability of various agents to interact with OCT2- or MATE1-mediated transport was determined using a recombinant vaccinia expression system. We were able to identify several drugs in clinical use with a divergent inhibitory capacity for these transporters. Subsequently, we further assessed the effect of those compounds on the cellular accumulation of shared substrates using OCT2 and MATE1 double-transfected cells. Consistent with data obtained using single transporter transfected cells, compounds that exhibited preferential inhibition of MATE1 such as rapamycin and mitoxantrone induced significant cellular accumulation of cationic substrates. We next assessed the functional relevance of MATE1 genetic polymorphisms. Significant loss of transport activity for metformin and tetraethylammonium was noted for two nonsynonymous single nucleotide polymorphisms (SNPs), c.404T>C (p.159T>M) and c.1012G>A (p.338V>A). The c.404T>C was only seen in Asian subjects with an allele frequency of 1%, and the c.1012G>A SNP was much more common, especially among those of African descent. In conclusion, we show that coordinate function of MATE1 with OCT2 likely contributes to the vectorial renal elimination of organic cationic drugs and that altered activity of MATE1, whether by drugs or polymorphisms, should be considered as an important determinant of renal cationic drug elimination.
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Zaharenko, Linda, Ineta Kalnina, Kristine Geldnere, Ilze Konrade, Solveiga Grinberga, Jozef Židzik, Martin Javorský, et al. "Single nucleotide polymorphisms in the intergenic region between metformin transporter OCT2 and OCT3 coding genes are associated with short-term response to metformin monotherapy in type 2 diabetes mellitus patients." European Journal of Endocrinology 175, no. 6 (December 2016): 531–40. http://dx.doi.org/10.1530/eje-16-0347.
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Objective(s) High variability in clinical response to metformin is often observed in type 2 diabetes (T2D) patients, and it highlights the need for identification of genetic components affecting the efficiency of metformin therapy. Aim of this observational study is to evaluate the role of tagSNPs (tagging single nucleotide polymorphisms) from genomic regions coding for six metformin transporter genes with respect to the short-term efficiency. Design 102 tagSNPs in 6 genes coding for metformin transporters were genotyped in the group of 102 T2D patients treated with metformin for 3 months. Methods Most significant hits were analyzed in the group of 131 T2D patients from Slovakia. Pharmacokinetic study in 25 healthy nondiabetic volunteers was conducted to investigate the effects of identified polymorphisms. Results In the discovery group of 102 patients, minor alleles of rs3119309, rs7757336 and rs2481030 were significantly nominally associated with metformin inefficiency (P = 1.9 × 10−6 to 8.1 × 10−6). Effects of rs2481030 and rs7757336 did not replicate in the group of 131 T2DM patients from Slovakia alone, whereas rs7757336 was significantly associated with a reduced metformin response in combined group. In pharmacokinetic study, group of individuals harboring risk alleles of rs7757336 and rs2481030 displayed significantly reduced AUC∞ of metformin in plasma. Conclusions For the first time, we have identified an association between the lack of metformin response and SNPs rs3119309 and rs7757336 located in the 5′ flanking region of the genes coding for Organic cation transporter 2 and rs2481030 located in the 5′ flanking region of Organic cation transporter 3 that was supported by the results of a pharmacokinetic study on 25 healthy volunteers.
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Chen, Rong, Bih Fang Pan, Mamoru Sakurai, and J. Arly Nelson. "A nucleoside-sensitive organic cation transporter in opossum kidney cells." American Journal of Physiology-Renal Physiology 276, no. 2 (February 1, 1999): F323—F328. http://dx.doi.org/10.1152/ajprenal.1999.276.2.f323.
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Renal secretion of organic cations and anions are pleiotropic, active processes in mammals. Some nucleosides such as deoxyadenosine (dAdo), 2-chlorodeoxyadenosine, and azidothymidine are secreted by human and rodent kidneys. Previous work (J. A. Nelson, J. F. Kuttesch, Jr., and B. H. Herbert. Biochemical Pharmacology 32: 2323–2327, 1983) indicated a role for the classic organic cation transporter (OCT) in the secretion of the dAdo analog, 2′-deoxytubercidin, by mouse kidney. Using [14C]tetraethylammonium bromide ([14C]TEA) as a substrate, we tested several renal cell lines for a nucleoside-sensitive OCT. American opossum kidney proximal tubule cells (OK) express a cimetidine-sensitive and metabolic-dependent ability to efflux TEA. Other classic OCT inhibitors and several nucleosides also inhibit TEA efflux by these cells in a manner reflecting structural specificity for the carrier. Inhibition of OCT by nucleosides is not a universal feature of OCTs, since TEA transport mediated by cloned rat kidney OCT2 in the Xenopus laevisoocyte system was not inhibited by the same nucleosides. In conclusion, OK cells appear to possess an OCT that may also transport some nucleosides by a novel carrier.
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Jeon, Ji-Hyeon, Sowon Lee, Wonpyo Lee, Sojeong Jin, Mihwa Kwon, Chul Hwi Shin, Min-Koo Choi, and Im-Sook Song. "Herb–Drug Interaction of Red Ginseng Extract and Ginsenoside Rc with Valsartan in Rats." Molecules 25, no. 3 (January 31, 2020): 622. http://dx.doi.org/10.3390/molecules25030622.
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The purpose of this study was to investigate the herb–drug interactions involving red ginseng extract (RGE) or ginsenoside Rc with valsartan, a substrate for organic anion transporting polypeptide (OATP/Oatp) transporters. In HEK293 cells overexpressing drug transporters, the protopanaxadiol (PPD)-type ginsenosides- Rb1, Rb2, Rc, Rd, Rg3, compound K, and Rh2-inhibited human OATP1B1 and OATP1B3 transporters (IC50 values of 7.99–68.2 µM for OATP1B1; 1.36–30.8 µM for OATP1B3), suggesting the herb–drug interaction of PPD-type ginsenosides involving OATPs. Protopanaxatriol (PPT)-type ginsenosides-Re, Rg1, and Rh1-did not inhibit OATP1B1 and OATP1B3 and all ginsenosides tested didn’t inhibit OCT and OAT transporters. However, in rats, neither RGE nor Rc, a potent OATP inhibitor among PPD-type ginsenoside, changed in vivo pharmacokinetics of valsartan following repeated oral administration of RGE (1.5 g/kg/day for 7 days) or repeated intravenous injection of Rc (3 mg/kg for 5 days). The lack of in vivo herb–drug interaction between orally administered RGE and valsartan could be attributed to the low plasma concentration of PPD-type ginsenosides (5.3–48.4 nM). Even high plasma concentration of Rc did not effectively alter the pharmacokinetics of valsartan because of high protein binding and the limited liver distribution of Rc. The results, in conclusion, would provide useful information for herb–drug interaction between RGE or PPD-type ginsenosides and Oatp substrate drugs.
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Erben, Philipp, Benjamin Hanfstein, Umang Munjal, Hannah Daikeler, Mridul Agrawal, Juliana Popa, Daniel Nowak, et al. "Pretreatment Expression Levels of MDR1 and OCT-1 Predict Response to First Line Imatinib Treatment In Chronic Phase CML Patients." Blood 116, no. 21 (November 19, 2010): 671. http://dx.doi.org/10.1182/blood.v116.21.671.671.
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Abstract Abstract 671 Introduction: The goal of imatinib therapy in newly diagnosed CML patients is the rapid achievement of cytogenetic and molecular responses. However, suboptimal response or resistance occur in a significant proportion of patients. BCR-ABL kinase domain mutations and various BCR-ABL independent mechanisms, such as clonal evolution are considered as leading causes of resistance and progression. It has been shown that imatinib efficacy depends on intracellular drug levels which are influenced by the activity of the human organic cation transporter 1 (OCT-1) influx protein and the multidrug resistance 1 (MDR1) efflux transporter protein. We therefore assessed the predictive significance of MDR1 and OCT-1 expression levels for molecular and cytogenetic response of chronic phase CML patients on first line imatinib treatment. Methods: A cohort of 170 newly diagnosed chronic phase CML patients (68 female, median age 53 years, range 19–79) treated with imatinib 400 mg/day in the German CML-Study IV were investigated. Multidrug resistance 1 efflux transporter protein (MDR1) and human organic cation transporter 1 (OCT-1) mRNA expression levels were determined by quantitative reverse transcription PCR using LightCycler™ technology and normalized against beta-glucuronidase (GUS) expression. Cytogenetic response was determined by G-banding metaphase analyses. Cut-off levels were defined by minimizing p-values. The Log-rank test (LR) and Gehan-Breslow-Wilcoxon test (GB) were performed to compare the time to major molecular remission (MMR) and complete cytogenetic remission (CCyR). Results: CCyR was achieved after a median of 6 months (range 3–42), MMR (BCR-ABL levels ≤0.1% on the International Scale) was achieved after a median of 13 months (range 3–43). Further, a significantly higher MMR and CCyR rates were observed in patients with high MDR1 and OCT-1 expression compared to patients with low MDR1 and OCT-1 expression. In addition, a prognostic score resulting in a three group stratification: Good risk, high MDR1 and high OCT-1 expression; intermediate risk, high MDR1 or high OCT-1 expression; poor risk, low MDR1 and low OCT-1 expression was also determined. MMR and CCyR rates were significantly higher in good risk compared to poor risk patients (Table). Conclusions: Pretreatment expression levels of MDR1 and OCT-1 appear to predict the achievement of MMR and CCyR under imatinib therapy in chronic phase CML patients over a period of 2 years of therapy. These findings might allow risk stratification in order to tailor the individualized first line therapy in CML. Disclosures: Erben: Novartis: Honoraria, Research Funding. Hochhaus:Novartis, BMS: Consultancy, Honoraria, Research Funding. Mueller:Novartis, BMS: Honoraria, Research Funding.
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TAKEDA, MICHIO. "Transporter; 4. Organic Anion Transporter (OAT)." Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics 35, no. 2 (2004): 67–73. http://dx.doi.org/10.3999/jscpt.35.2_67.
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Gonome, Takayuki, Yuting Xie, Saeko Arai, Kodai Yamauchi, Natsuki Maeda-Monai, Reiko Tanabu, Takashi Kudo, and Mitsuru Nakazawa. "Excess Glutamate May Cause Dilation of Retinal Blood Vessels in Glutamate/Aspartate Transporter-Deficient Mice." BioMed Research International 2019 (November 11, 2019): 1–11. http://dx.doi.org/10.1155/2019/6512195.
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Purpose. To investigate the longitudinal findings of fundus features and spectral-domain optical coherence tomography (SD-OCT) to characterize the morphologic features in a mouse model of defective glutamate/aspartate transporter (GLAST−/− mice). Materials and Methods. The fundus findings and SD-OCT images were longitudinally recorded at five time points from postnatal (P) 22 to P156 in GLAST−/− mice. As a control wild type, age-matched C57BL/6J mice were employed. The mouse retina was subdivided into five layers, and the thickness of each layer was longitudinally measured by InSight® using SD-OCT pictures. The SD-OCT findings were compared with the histologic appearances. The diameter of the retinal blood vessels was measured by the ImageJ® software program using SD-OCT images. The data were statistically compared between both age-matched mouse groups. Results. The retinal blood vessels appeared more dilated in GLAST−/− mice than in wild-type mice. This tendency was statistically significant at all time points after P44 by analyses using SD-OCT images. The ganglion cell complex (GCC) and outer nuclear layer (ONL) were significantly thinner in GLAST−/− mice at all time points after P80 than in the wild-type mice. This tendency was more clearly indicated by SD-OCT than histologic sections. Discussion. In the present study, we found for the first time the dilation of the retinal blood vessels and the thinning of the ONL in GLAST−/− mice, in addition to the thinning of the GCC.
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Gründemann, Dirk, Christian Hahne, Reinhard Berkels, and Edgar Schömig. "Agmatine Is Efficiently Transported by Non-Neuronal Monoamine Transporters Extraneuronal Monoamine Transporter (EMT) and Organic Cation Transporter 2 (OCT2)." Journal of Pharmacology and Experimental Therapeutics 304, no. 2 (February 1, 2003): 810–17. http://dx.doi.org/10.1124/jpet.102.044404.
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Motohashi, Hideyuki, Yuji Sakurai, Hideyuki Saito, Satohiro Masuda, Yumiko Urakami, Maki Goto, Atsushi Fukatsu, Osamu Ogawa, and Ken-ichi Inui. "Gene Expression Levels and Immunolocalization of Organic Ion Transporters in the Human Kidney." Journal of the American Society of Nephrology 13, no. 4 (April 2002): 866–74. http://dx.doi.org/10.1681/asn.v134866.
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ABSTRACT. Renal excretion of organic anions and cations is mediated by the organic ion transporter family (SLC22A). In this study, the mRNA levels of the organic ion transporters were quantified by real-time PCR in normal parts of renal tissues from seven nephrectomized patients with renal cell carcinoma, and the distributions and localization of human (h)OAT1, hOAT3, and hOCT2 proteins were investigated by immunohistochemical analyses in the human kidney. The expression level of hOAT3 mRNA was the highest among the organic ion transporter family, followed by that of hOAT1 mRNA. The hOCT2 mRNA level was the highest in the human OCT family, and the level of hOCTN2 mRNA was higher than that of hOCTN1. hOCT1 mRNA showed the lowest level of expression in organic ion transporter family. hOAT1, hOAT3, and hOCT2 proteins were detected in crude membranes from the kidney of all patients by Western blot analyses, whereas hOCT1 protein could not be detected. Immunohistochemical analyses showed that both hOAT1 and hOAT3 were localized to the basolateral membrane of the proximal tubules in the cortex, and hOCT2 was localized to the basolateral membrane of the proximal tubules in both the cortex and medullary ray. Immunohistochemical analyses of serial sections indicated that hOAT1, hOAT3, and hOCT2 were coexpressed in a portion of the proximal tubules. These results suggest that hOAT1, hOAT3, and hOCT2 play predominant roles in the transport of organic ions across the basolateral membrane of human proximal tubules.
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Vollmar, Johanna, Yong Ook Kim, Jens U. Marquardt, Diana Becker, Peter R. Galle, Detlef Schuppan, and Tim Zimmermann. "Deletion of organic cation transporter Oct3 promotes hepatic fibrosis via upregulation of TGFβ." American Journal of Physiology-Gastrointestinal and Liver Physiology 317, no. 2 (August 1, 2019): G195—G202. http://dx.doi.org/10.1152/ajpgi.00088.2019.
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Organic cation transporters (OCT) are responsible for the intracellular uptake and detoxification of a broad spectrum of endogenous and exogenous substrates. OCTs are downregulated in cholestasis, fibrosis, and hepatocellular carcinoma, but the underlying molecular mechanisms and downstream effects of OCT deletion are unknown. Oct3-knockout ( Oct3−/−; FVB.Slc22a3tm10pb) and wild-type (WT; FVB) mice were subject to escalating doses of carbon tetrachloride (CCl4) or thioacetamide (TAA) for 6 wk to induce advanced parenchymal liver fibrosis. Secondary biliary fibrosis was generated by bile duct ligation. Liver fibrosis was assessed by hydroxyproline determination, quantitative Sirius red morphometry, and quantitative real-time PCR for fibrosis and inflammation-related genes. Ductular reaction was assessed by bile duct count per field of view in hematoxylin and eosin staining. General gene expression analyses were performed in liver tissue from untreated Oct3−/− and WT mice. Finally, primary murine hepatocytes were treated with the nonselective OCT inhibitor quinine, and transforming growth factor-β1 ( Tgfβ1) protein expression was quantified by quantitative real-time PCR and Western blot. Oct3−/− mice developed significantly more fibrosis after bile duct ligation and CCl4 treatment compared with WT mice. Ductular reaction was enhanced in the long-term model. Concomitantly, Oct1 mRNA expression was downregulated during cholestatic and chemically (TAA and CCl4) induced fibrogenesis. The downregulation of Oct1 mRNA in fibrotic liver tissue reversed within 4 wk after TAA cessation. Gene expression analysis by next-generation sequencing revealed an enrichment of Tgfβ1 target genes in Oct3−/− mice. Tgfβ1 mRNA expression was significantly upregulated after chemically induced fibrosis ( P < 0.001) in Oct3−/− compared with WT mice. Accordingly, in primary murine hepatocytes functional inhibition of OCT led to an upregulation of Tgfβ1 mRNA expression. Loss of Oct3 promotes fibrogenesis by affecting Tgfβ-mediated homeostasis in mice with chronic biliary and parenchymal liver damage and fibrosis. NEW & NOTEWORTHY We show for the first time that organic cation transporter 3 (Oct3) is not only downregulated in fibrosis but loss of Oct3 also leads to an upregulation of transforming growth factor-β contributing to fibrosis progression.
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White, Deborah, Phuong Dang, Kelvin Groot Obbink, Amity Frede, Chung Kok, Timothy P. Hughes, and Richard D’Andrea. "Enhancing the Functional Activity of the OCT-1 Influx Pump May Overcome the Negative Impact of Low OCT-1 Activity in Imatinib Treated CML Patients." Blood 112, no. 11 (November 16, 2008): 723. http://dx.doi.org/10.1182/blood.v112.11.723.723.
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Abstract The human organic cation transporter-1 (hOCT-1) is the major active influx protein responsible for the transport of imatinib into blood cells 1,2. The functional activity of the OCT-1 protein is defined as the intracellular uptake and retention (IUR) of 14-C labelled imatinib into patient pre therapy mononuclear blood cells over a two hour period, which is inhibited by OCT-1 inhibitors such as prazosin or procainamide. The level of OCT-1 activity is a key determinant of the interpatient variation observed in intrinsic sensitivity to imatinib induced kinase inhibition (IC50imatinib3). We have previously demonstrated that a significantly greater proportion of de-novo CML patients with high functional activity of OCT-1, achieve a major molecular response (MMR: 3 log reduction in BCR-ABL mRNA from standardised baseline) when treated with imatinib, than patients with low OCT-1 Activity 4. We have also identified a link between dose and OCT-1 Activity, demonstrating that the negative impact of low OCT-1 Activity could be overcome to a variable extent by imatinib dose increase. However, not all patients can dose increase, largely because of tolerability issues. While the transport of second-generation ABL-kinase inhibitors (nilotinib and dasatinib5) is not OCT-1 mediated, the long term effect of these drugs is not yet known. Hence, we sought to identify strategies to increase OCT-1-mediated imatinib uptake. We queried the drug gene expression signatures in version 1 of the Connectivity Map (CMAP; Lamb J, Nat. Rev. Cancer7; 54–60, 2007: http://www.broad.mit.edu/cmap) with 3 transporters including OCT-1. This identified the Rho kinase inhibitor fasudil and COX-2 inhibitor / celecoxib analogue LM1685 as potential up-regulators of OCT-1 mRNA. The impact of these drugs on OCT-1 mRNA expression and IC50imatinib (fasudil alone to date) has been analysed in two bcr-abl positive cell lines (K562 and KU812). The effect of these two candidate OCT-1 enhancers on OCT-1-mediated imatinib uptake was also assessed in 10 newly diagnosed chronic phase CML patients, previously demonstrated to have low OCT-1 Activity (4 with no demonstrable OCT-1 Activity), using the IUR assay. Table 1: Assessing the effects of fasudil and LM1685 on the intracellular transport of imatinib. These data demonstrate a statistically significant increase in OCT-1 Activity with LM1685, and show a strong trend towards significance with fasudil. Importantly, we show that patients with no demonstrable OCT-1 Activity (0ng/200,000 cells) have detectable Activity in the presence of both fasudil (Range 1.5 to 2ng/200,000 cells) and LM1685 (Range 1.5 to 4.5 ng/200,000 cells). We have previously demonstrated that patients with no detectable OCT-1 Activity universally fail to achieve imatinib therapeutic response milestones (imatinib failure), whereas 54% of patients with low, but detectable OCT-1 Activity achieve these milestones4. The ability to enhance the functional activity of the OCT-1 protein may therefore be of significant clinical relevance in this group. In addition we demonstrate an increase in imatinib IUR which, along with the increase in OCT-1 Activity, is likely associated with increased OCT-1 mRNA levels. Significantly, in the two CML cell lines tested we show a marked reduction in the IC50imatinib indicating that the observed increase in IUR and OCT-1 Activity translates to an increase in the kinase inhibitory activity of imatinib. Preliminary analysis in one patient analysed to date also indicates a reduction in IC50 from 0.48 to 0.35μM in the presence of fasudil. In the clinical scenario the use of such OCT-1 enhancers may improve the response of some imatinib treated patients to both standard and increased dose imatinib. Importantly, these findings validate the use of resources such as C-MAP to identify candidate drugs that may mediate desired changes in the levels of key proteins resulting in improved response to therapy. Fasudil (10μM) %increase from control LM1685 (1μM) % increase from control IUR of imatinib OCT-1 Activity IC50imatinib IUR of imatinib OCT-1 Activity K562 76% (n=5) 163% (n=5) 51% reduction (n=3) 41% (n=2) 122% (n=2) KU812 10.7% (n=2) 75% (n=2) 15% reduction (n=2) NA NA CML patients n=10 8% 89% 9% 114% p value >0.05 0.08 >0.05 0.03
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Zaïr, Zoulikha M., Jyrki J. Eloranta, Bruno Stieger, and Gerd A. Kullak-Ublick. "Pharmacogenetics of OATP (SLC21/SLCO), OAT and OCT (SLC22) and PEPT (SLC15) transporters in the intestine, liver and kidney." Pharmacogenomics 9, no. 5 (May 2008): 597–624. http://dx.doi.org/10.2217/14622416.9.5.597.
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Choi, Min-Koo, and Im-Sook Song. "Genetic variants of organic cation transporter 1 (OCT1) and OCT2 significantly reduce lamivudine uptake." Biopharmaceutics & Drug Disposition 33, no. 3 (March 17, 2012): 170–78. http://dx.doi.org/10.1002/bdd.1783.
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Shikata, Eriko, Rei Yamamoto, Hiroshi Takane, Chiaki Shigemasa, Tadasu Ikeda, Kenji Otsubo, and Ichiro Ieiri. "Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin." Journal of Human Genetics 52, no. 2 (November 17, 2006): 117–22. http://dx.doi.org/10.1007/s10038-006-0087-0.
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Engler, Jane R., Amity Frede, Andrew C. W. Zannettino, Deborah L. White, and Timothy P. Hughes. "Reduced Activity of the OCT-1 Protein in Primitive CML Cells: A Likely Determinant of Stem Cell Resistance in Imatinib Treated CML Patients." Blood 112, no. 11 (November 16, 2008): 196. http://dx.doi.org/10.1182/blood.v112.11.196.196.
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Abstract Despite cytogenetic and molecular remissions, residual chronic myeloid leukemia (CML) cells persist in the primitive CD34+ compartment in the majority of imatinib treated patients. It has been demonstrated that CD34+ CML cells have a reduced sensitivity to imatinib induced apoptosis. Factors which may contribute to this reduced sensitivity are reduced dependence on BCR-ABL, an increase in BCR-ABL transcripts, increased expression of efflux proteins or decreased expression of drug influx proteins. Our previous studies show that a patient’s intrinsic sensitivity to imatinib-induced kinase inhibition (IC50) is related to the intracellular uptake and retention (IUR) of imatinib in peripheral blood mononuclear cells. The organic cation transporter 1 (OCT-1) is the major active influx transporter for imatinib in these cells, and the functional activity of this protein (determined using functional inhibition of OCT-1, in the IUR assay) directly correlates with molecular response to imatinib. In the present study we investigated the role that OCT-1 plays in stem cell resistance to imatinib. Primitive CD34+ and mature CD34− cells were isolated from CML patients and normal individuals using magnetic cell sorting. CML CD34+ cells had a significantly lower IURimatinib than that of CML CD34− cells (Table 1). The addition of the OCT-1 inhibitor, prazosin (100μM), eliminated this difference in IUR (Table 1), indicating that variation in IURimatinib is due to variation in the functional activity of the OCT-1 protein. In addition, the OCT-1 Activity (Table 1) and OCT-1 mRNA expression (expressed as % of BCR: mean CD34+=0.25; CD34−=4.9, p=0.040, n=10) was significantly lower in CML CD34+ cells compared with CML CD34− cells. These differences in IURimatinib and OCT-1 activity between CD34+ and CD34− cells were not observed in normal individuals (Table 1), suggesting this phenomenon is specific to leukemic cells. Furthermore, we isolated the more primitive compartment, CD34+38− cells and less primitive CD34+38+ cells in 4 CML patients. The CD34+38− cells demonstrated a 13% reduction in IURimatinib and a 41% reduction in OCT-1 activity compared with CD34+38+ cells. These data suggest a reduced IUR mediated by low OCT-1 function and/or expression may play a role in the resistance of CML stem cells to imatinib. Table 1: The IUR of 2μM imatinib expressed as ng/200,000 cells (standard deviation) n Imatinib IUR P value + Prazosin P value OCT-1 Activity P value CML CD34+ 14 16.05 (4.53) 0.002 13.02 (3.34) 0.505 3.25 (2.32) <0.001 CML CD34− 14 27.28 (12.92) 14.76 (5.25) 14.01 (12.08) Normal CD34+ 11 11.13 (2.66) 0.212 10.43 (3.80) 0.743 2.03 (2.09) 0.693 Normal CD34− 11 13.92 (5.32) 10.93 (3.30) 3.52 (5.24) Increased expression of efflux transporters of imatinib (i.e. ABCB1 and ABCG2) has been suggested as an important mechanism for drug resistance. The effect of an ABCB1 inhibitor (PSC833) and ABCG2 inhibitor (Ko143) was assessed in CD34+ cells from 3 CML patients, using the IUR assay. Neither of these drugs had any effect on the IURimatinib in CML CD34+ cells. Additionally the mRNA expression of ABCB1 did not differ between CML CD34+ and CD34− cells (expressed as a % of BCR: mean CD34+=33.7; CD34−=33.77, p=0.064, n=10). These data suggest that alterations in imatinib influx (via OCT-1) are more critical for development of stem cell resistance rather than differences in efflux. We have previously demonstrated that, unlike imatinib, the OCT-1 protein is not involved in nilotinib transport, as the addition of OCT-1 inhibitors does not alter IURnilotinib in patients. Assessing the IUR of nilotinib in CD34+ and CD34− CML cells reveals no significant difference between the two populations (Table 2). Additionally, the IURnilotinib is significantly higher than IURimatinib in CML CD34+ cells (Table 2). In summary, the reduced OCT-1 mediated uptake of imatinib in more primitive, CD34+ CML cells may result in inadequate kinase inhibition and contribute to stem cell resistance in CML. Since nilotinib uptake into CML CD34+ cells is not impaired in the same manner as imatinib, more substantial depletion of the primitive CML cells may be achieved. Table 2: The IUR of 2μM imatinib and nilotinib in the same 11 CML patients. Expressed as ng/200,000 cells (standard deviation) n Imatinib IUR P value Nilotinib IUR P value P value between imatinib & nilotinib IUR CML CD34+ 11 17.80 (5.73) 0.006 26.35 (7.54) 0.230 0.007 CML CD34− 11 30.28 (12.33) 22.05 (8.68) 0.076
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St-Pierre, M. V., T. Stallmach, A. Freimoser Grundschober, J. F. Dufour, M. A. Serrano, J. J. G. Marin, Y. Sugiyama, and P. J. Meier. "Temporal expression profiles of organic anion transport proteins in placenta and fetal liver of the rat." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 287, no. 6 (December 2004): R1505—R1516. http://dx.doi.org/10.1152/ajpregu.00279.2003.
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Physiological cholestasis linked to immature hepatobiliary transport systems for organic anions occurs in rat and human neonates. In utero, the placenta facilitates vectorial transfer of certain fetal-derived solutes to the maternal circulation for elimination. We compared the ontogenesis of organic anion transporters in the placenta and the fetal liver of the rat to assess their relative abundance throughout gestation and to determine whether the placenta compensates for the late maturation of transporters in the developing liver. The mRNA of members of the organic anion transporting polypeptide (Oatp) superfamily, the multidrug resistance protein (Mrp) family, one organic anion transporter (OAT), and the bile acid carriers Na+-taurocholate cotransporting polypeptide (Ntcp) and bile salt export pump (Bsep) was quantified by real-time PCR. The most abundant placental transporters were Oatp4a1, whose mRNA increased 10-fold during gestation, and Mrp1. Mrp1 immunolocalized predominantly to epithelial cells of the endoplacental yolk sac, suggesting an excretory role that sequesters fetal-derived solutes in the yolk sac cavity, and faintly to the basal syncytiotrophoblast surface. The mRNA levels of Oatp2b1, Mrp3, and Bsep in the placenta exceeded those in the fetal liver until day 20 of gestation, suggesting that the fetus relies on placental clearance of substrates when expression in the developing liver is low. Mrp3 immunolocalized to the epithelium of the endoplacental yolk sac and less abundantly in the labyrinth zone and endothelium of the maternal arteries. The placental expression of Oatp1a1, Oatp1a4, Oatp1a5, Oatp1b2, Oat, Ntcp, Mrp2, and Mrp6 was low.
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Jin, Sojeong, Sowon Lee, Ji-Hyeon Jeon, Hyuna Kim, Min-Koo Choi, and Im-Sook Song. "Enhanced Intestinal Permeability and Plasma Concentration of Metformin in Rats by the Repeated Administration of Red Ginseng Extract." Pharmaceutics 11, no. 4 (April 18, 2019): 189. http://dx.doi.org/10.3390/pharmaceutics11040189.
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We aimed to assess the potential herb–drug interactions between Korean red ginseng extract (RGE) and metformin in rats in terms of the modulation of metformin transporters, such as organic cation transporter (Oct), multiple toxin and extrusion protein (Mate), and plasma membrane monoamine transporter (Pmat). Single treatment of RGE did not inhibit the in vitro transport activity of OCT1/2 up to 500 µg/mL and inhibited MATE1/2-K with high IC50 value (more than 147.8 µg/mL), suggesting that concomitant used of RGE did not directly inhibit OCT- and MATE-mediated metformin uptake. However, 1-week repeated administration of RGE (1.5 g/kg/day) (1WRA) to rats showed different alterations in mRNA levels of Oct1 depending on the tissue type. RGE increased intestinal Oct1 but decreased hepatic Oct1. However, neither renal Oct1/Oct2 nor Mate1/Pmat expression in duodenum, jejunum, ileum, liver, and kidney were changed in 1WRA rats. RGE repeated dose also increased the intestinal permeability of metformin; however, the permeability of 3-O-methyl-d-glucose and Lucifer yellow was not changed in 1WRA rats, suggesting that the increased permeability of metformin by multiple doses of RGE is substrate-specific. On pharmacokinetic analysis, plasma metformin concentrations following intravenous injection were not changed in 1WRA, consistent with no significant change in renal Oct1, Oct2, and mate1. Repeated doses of RGE for 1 week significantly increased the plasma concentration of metformin, with increased half-life and urinary excretion of metformin following oral administration of metformin (50 mg/kg), which could be attributed to the increased absorption of metformin. In conclusion, repeated administration of RGE showed in vivo pharmacokinetic herb–drug interaction with metformin, with regard to its plasma exposure and increased absorption in rats. These results were consistent with increased intestinal Oct1 and its functional consequence, therefore, the combined therapeutic efficacy needs further evaluation before the combination and repeated administration of RGE and metformin, an Oct1 substrate drug.