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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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Müller, Johanna, Katrin S. Lips, Linda Metzner, Reinhard H. H. Neubert, Hermann Koepsell, and Matthias Brandsch. "Drug specificity and intestinal membrane localization of human organic cation transporters (OCT)." Biochemical Pharmacology 70, no. 12 (December 2005): 1851–60. http://dx.doi.org/10.1016/j.bcp.2005.09.011.
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Keiser, Markus, Mahmoud Hasan, and Stefan Oswald. "pH-Dependent affinity of ketamine to P-GP, OCT and MATE transporters." Drug Metabolism and Pharmacokinetics 33, no. 1 (January 2018): S91—S92. http://dx.doi.org/10.1016/j.dmpk.2017.11.298.
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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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Visentin, Michele, Belle V. van Rosmalen, Christian Hiller, Matthanja Bieze, Lia Hofstetter, Joanne Verheij, Gerd A. Kullak-Ublick, et al. "Impact of Organic Cation Transporters (OCT-SLC22A) on Differential Diagnosis of Intrahepatic Lesions." Drug Metabolism and Disposition 45, no. 2 (November 30, 2016): 166–73. http://dx.doi.org/10.1124/dmd.116.072371.
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Atreya, PN, and A. Kafle. "Production practice, market and value chain study of organic apple of Jumla." Journal of Agriculture and Environment 17 (May 7, 2018): 11–23. http://dx.doi.org/10.3126/aej.v17i0.19855.
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This study was undertaken to explore the market and value chain of apple in Jumla and Nepaljung in January 2014. Primary and secondary data were used for this study. All together 10 respondent farmers were selected for production related data, five retailers from Jumla and Nepaljung, one wholesaler from Nepaljung and 10 consumers for market study. Highest wholesale price was observed in May/June - June/July (NRs. 145/kg) while lowest was in Sept./Oct.-Oct./Nov. (NRs. 83/kg). Similarly highest retail price (NRs. 185/kg) was in the month of June/July and lowest (NRs. 115/Kg) was in Sept./Oct-Oct./Nov. The average farm gate price of apple is too low (NRs.26.93/kg) as compared to wholesale, retail and consumers prices. The producers, traders, transporters, wholesalers and retailers were the main marketing actors of apple. Contractual system before and during production were observed in marketing. Price spread of Jumla apple was assessed with the different actors (contractors, traders, wholesalers, retailers and consumers) in value chain. Apple is the major commodity for income generation so better knowledge on production marketing and value addition through processing should be imparted to the farmers.
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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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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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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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Milunović, Miljan N. M., Oleg Palamarciuc, Angela Sirbu, Sergiu Shova, Dan Dumitrescu, Dana Dvoranová, Peter Rapta, et al. "Insight into the Anticancer Activity of Copper(II) 5-Methylenetrimethylammonium-Thiosemicarbazonates and Their Interaction with Organic Cation Transporters." Biomolecules 10, no. 9 (August 20, 2020): 1213. http://dx.doi.org/10.3390/biom10091213.
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A series of four water-soluble salicylaldehyde thiosemicarbazones with a positively charged trimethylammonium moiety ([H2LR]Cl, R = H, Me, Et, Ph) and four copper(II) complexes [Cu(HLR)Cl]Cl (1–4) were synthesised with the aim to study (i) their antiproliferative activity in cancer cells and, (ii) for the first time for thiosemicarbazones, the interaction with membrane transport proteins, specifically organic cation transporters OCT1–3. The compounds were comprehensively characterised by analytical, spectroscopic and X-ray diffraction methods. The highest cytotoxic effect was observed in the neuroblastoma cell line SH-5YSY after 24 h exposure and follows the rank order: 3 > 2 > 4 > cisplatin > 1 >> [H2LR]Cl. The copper(II) complexes showed marked interaction with OCT1–3, comparable to that of well-known OCT inhibitors (decynium 22, prazosin and corticosterone) in the cell-based radiotracer uptake assays. The work paves the way for the development of more potent and selective anticancer drugs and/or OCT inhibitors.
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Ceckova, Martina, Josef Reznicek, Birgit Deutsch, Martin F. Fromm, and Frantisek Staud. "Efavirenz reduces renal excretion of lamivudine in rats by inhibiting organic cation transporters (OCT, Oct) and multidrug and toxin extrusion proteins (MATE, Mate)." PLOS ONE 13, no. 8 (August 16, 2018): e0202706. http://dx.doi.org/10.1371/journal.pone.0202706.
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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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Fahrmayr, Christina, Martin F. Fromm, and Jörg König. "Hepatic OATP and OCT uptake transporters: their role for drug-drug interactions and pharmacogenetic aspects." Drug Metabolism Reviews 42, no. 3 (January 25, 2010): 380–401. http://dx.doi.org/10.3109/03602530903491683.
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Kindla, Jürgen, Martin F. Fromm, and Jörg König. "In vitroevidence for the role of OATP and OCT uptake transporters in drug–drug interactions." Expert Opinion on Drug Metabolism & Toxicology 5, no. 5 (May 2009): 489–500. http://dx.doi.org/10.1517/17425250902911463.
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Parvez, MD Masud, Jin-Ah Jung, Jae-Eun Kim, Ho Jung Shin, Su Jung Lim, Mun Ju Cho, Yeon Jeong Yoon, Dong Jun Lee, Dong-Hyun Kim, and Jae-Gook Shin. "Characterization of 22 anti-tuberculosis drugs for the inhibitory effect on OAT and OCT transporters mediated uptake; possibility of drug-drug interactions." Drug Metabolism and Pharmacokinetics 32, no. 1 (January 2017): S98—S99. http://dx.doi.org/10.1016/j.dmpk.2016.10.378.
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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.
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Moreira-Nnes, Caroline Fátima Aquino, Ana Cristina Simões Beltrão, Tereza Cristina Brito Azevedo, Larissa Tatiana Valente Martins Francês, Rodrigo Guarischi Mattos Amaral Sousa, Israel Tojal Silva, Artur Luiz Costa Silva, Wilson Araújo Silva-Jr, and José Alexandre Rodrigues Lemos. "Transcriptome of Expressed Genes in CD34+ and CD66b+ Chronic Myeloid Leukemia Cells and Its Potential Role in the Transport of Kinase Inhibitors." Blood 118, no. 21 (November 18, 2011): 4426. http://dx.doi.org/10.1182/blood.v118.21.4426.4426.
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Abstract Abstract 4426 Background. Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder characterized by Phildaelphia chromosome and by formation of BCR-ABL fusion. Some studies have shown that residual cells are part of the leukemic cells undifferentiated compartment. In 2005, Michor et al. (Nature 435: 1267–1270), through mathematical model, concluded that imatinib efficiently reduces the differentiated leukemic cells population, but it has not the same effect on the cell population that drives this disease, the CD34+ leukemic stem cells, which can be kept alive during the treatment. However, Mahon et al. (Lancet Oncol 11: 1029–35, 2010) described a cohort in which patients remained disease free for 18 months after discontinued treatment. This finding is an indication that the leukemia stem cells (LSC) are not totally insensitive to kinase inhibitors (KIs). Purpose. Identify the expressed genes in CD34+ and CD66b+ cells as candidates for KIs transport. Methods. Samples of bone marrow (BM) and peripheral blood (PB) were obtained from five patients with CML treated with imatinib in optimal response in according to European LeukemiaNet criteria. Cells Isolation and RNA extraction. CD34+ cells were isolated from BM of five patients with CML. Mature CD66b+ PB cells were isolated from the same patients. SOLiD sequencing. cDNA was sequenced according to the manufacturer's protocols for the SOLiD. Transcriptome. Two libraries were constructed for this purpose and approximately 120 millions of beads were deposited on a half slide for each library and sequenced using the Opti Fragment Library Sequencing kit-Master Mix 50 on a SOLiD machine (Ver 3+). To characterize the genes showing differential regulation, we analyzed the Gene Ontology (GO) annotation associated with transporters genes exhibiting a greater than 2-fold difference in expression by RNA-seq. Analysis using the functional annotation clustering feature of DAVID. Results. We have sequenced 14.133 genes in CD34+ pool cells and 3.379 genes in CD66b+ pool cells, with 2.883 genes expressed in both. Of these, 1.201 genes from membrane transport were functionally annotated, and we have found 560 genes expressed exclusively in CD34+, and 99 genes in CD66b+, and 542 genes in both, as shown below. Regarding imatinib transportation, two major classes of transporters are widely recognized for its importance in drug influx and efflux inside the cell, the ATP-biding cassette transporters (ABC family) and Solute Carrier family (SLC family). Studies have demonstrated that the organic cation transporter 1 (OCT-1, also known as SLC22A1) is the major active influx transporter for imatinib in CML cells, in our study we find no evidence of OCT-1 in any of our samples, which may indicate that this is not the channel for the influx of drugs into cells. Within ABC family is already recognized the important function of at least three genes in multidrug-resistance cancer through the mechanism of drug efflux through the membrane, they are: ABCB1 (MDR1); ABCG2 (Breast Cancer Resistance Protein – BCRP) e ABCC1 (MRP1). These genes were found exclusively in the CD34+ lineage of CML patients, reinforcing the theory that HSC are resistant to treatment with imatinib, through the expression of efflux channels. Conclusion. The efflux channel genes exclusively expressed in CD34+ cells represents a major barrier to maintaining optimal response to KIs in long-term treatment of CML patients. Those genes should be investigated to achieve the development of drugs with potential to block the efflux channels and improve outcome for cancer patients. Disclosures: Lemos: Novartis Oncology: Research Funding.
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Park, Sohyeon, Yoonjin Park, Heejong Shin, Boyong Kim, and Seunggwan Lee. "Effect of Allium senescens Extract on Sorafenib Resistance in Hepatocarcinoma Cells." Applied Sciences 11, no. 8 (April 20, 2021): 3696. http://dx.doi.org/10.3390/app11083696.
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Although Allium species are involved in bioactivity, to the best of our knowledge, there is no research on the effects of Allium senescens on drug resistance in hepatocarcinoma. Ultra-high performance liquid chromatography was used to determine the concentration of several bioactive compounds in A. senescens extract; flow cytometry, reverse transcription–quantitative polymerase chain reaction, and siRNA-mediated knockdown to estimate the levels of different markers in HepG2 cells. The quantity of p-coumaric acid in the extract was 4.7291 ± 0.06 μg/mL, and the protein of relevant evolutionary and lymphoid interest (PRELI) in the resistant cells decreased 2.1 times in the presence of p-coumaric acid. The resistant cells strongly downregulated the efflux transporters (ABCB1, ABCC2, and ABCG2) when exposed to the extract or p-coumaric acid and when PRELI was knocked down, in contrast to the influx proteins (OCT-1). Additionally, the extract induced mitochondrial apoptosis and suppressed autophagy. Consequently, the extract and p-coumaric acid attenuated drug resistance of HepG2 cells through the downregulation of PRELI, a key protein associated with the modulation of drug transporter expression, the activation of autophagy, and mitochondrial apoptosis. Our results indicate that A. senescens extract is beneficial in protecting cancer cells against drug resistance and sustaining the efficacy of sorafenib against liver cancer.
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Meltzer, Peter C., Duy-Phong Pham-Huu, and Bertha K. Madras. "Synthesis of 8-thiabicyclo[3.2.1]oct-2-enes and their binding affinity for the dopamine and serotonin transporters." Bioorganic & Medicinal Chemistry Letters 14, no. 24 (December 2004): 6007–10. http://dx.doi.org/10.1016/j.bmcl.2004.09.080.
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Park, Jeong-eun, Jee-hye Choi, Tae-eun Kim, Hyeog-jung Kwon, and Kwang-Hee Shin. "Effect of geneticpolymorphism of OCT and mate transporters on metformin response in korean type 2 diabetes mellitus patients." Drug Metabolism and Pharmacokinetics 32, no. 1 (January 2017): S86. http://dx.doi.org/10.1016/j.dmpk.2016.10.335.
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Amrhein, Jan, Susanne Drynda, Lukas Schlatt, Uwe Karst, Christoph H. Lohmann, Giuliano Ciarimboli, and Jessica Bertrand. "Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA." International Journal of Molecular Sciences 21, no. 18 (September 10, 2020): 6632. http://dx.doi.org/10.3390/ijms21186632.
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Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease in which synovial fibroblasts (SF) play a key role. Baricitinib and Tofacitinib both act intracellularly, blocking the ATP-binding side of JAK proteins and thereby the downstream signalling pathway via STAT-3. Therefore, we investigated the role of organic cation transporters (OCTs) in Baricitinib and Tofacitinib cellular transport. Methods: OCT expression was analysed in SF isolated from RA and osteoarthritis (OA) patients, as well as peripheral blood mononuclear cells. The interaction of Baricitinib and Tofacitinib with OCTs was investigated using quenching experiments. The intracellular accumulation of both drugs was quantified using LC/MS. Target inhibition for both drugs was tested using Western blot for phosphorylated JAK1 and STAT3 upon stimulation with IL-6. Results: MATE-1 expression increased in OASF compared to RASF. The other OCTs were not differentially expressed. The transport of Baricitinib was not OCT dependent. Tofacitinib; however, was exported from RASF in a MATE-1 dependent way. Tofacitinib and Baricitinib showed comparable inhibition of downstream signalling pathways. Conclusion: We observed different cellular uptake strategies for Baricitinib and Tofacitinib. Tofacitinib was exported out of healthy cells due to the increased expression of MATE1. This might make Tofacitinib the favourable drug.
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Pabla, Navjotsingh, Robert F. Murphy, Kebin Liu, and Zheng Dong. "The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity." American Journal of Physiology-Renal Physiology 296, no. 3 (March 2009): F505—F511. http://dx.doi.org/10.1152/ajprenal.90545.2008.
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The usefulness and efficacy of cisplatin, a chemotherapeutic drug, are limited by its toxicity to normal tissues and organs, including the kidneys. The uptake of cisplatin in renal tubular cells is high, leading to cisplatin accumulation and tubular cell injury and death, culminating in acute renal failure. While extensive investigations have been focused on the signaling pathways of cisplatin nephrotoxicity, much less is known about the mechanism of cisplatin uptake by renal cells and tissues. In this regard, evidence has been shown for the involvement of organic cation transporters (OCT), specifically OCT2. The copper transporter Ctr1 is highly expressed in the renal tubular cells; however, its role in cisplatin nephrotoxicity is not known. In this study, we demonstrate that Ctr1 is mainly expressed in both proximal and distal tubular cells in mouse kidneys. We further show that Ctr1 is mainly localized on the basolateral side of these cells, a proposed site for cisplatin uptake. Importantly, downregulation of Ctr1 by small interfering RNA or copper pretreatment results in decreased cisplatin uptake. Consistently, downregulation of Ctr1 suppresses cisplatin toxicity, including cell death by both apoptosis and necrosis. Cimetidine, a pharmacological inhibitor of OCT2, can also partially attenuate cisplatin uptake. Notably, cimetidine can further reduce cisplatin uptake and cisplatin toxicity in Ctr1-downregulated cells. The results have demonstrated the first evidence for a role of Ctr1 in cisplatin uptake and nephrotoxicity.
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Hwang, Youn-Hwan, Won-Kyung Cho, Doorye Jang, Jeong-Ho Ha, Kiyoun Jung, Hyo-In Yun, and Jin Yeul Ma. "Effects of Berberine and Hwangryunhaedok-Tang on Oral Bioavailability and Pharmacokinetics of Ciprofloxacin in Rats." Evidence-Based Complementary and Alternative Medicine 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/673132.
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Hwangryunhaedok-Tang (HR) and berberine-containing single herbs are used to treat bacterial infection and inflammatory diseases in eastern Asia. The combination of berberine-containing herbal medicines and ciprofloxacin can be an excellent antibacterial chemotherapy against multidrug resistance bacteria. To evaluate the pretreatment effect of berberine and HR, vehicle, berberine (25 and 50 mg/kg/day), and HR (1.4 g/kg/day) were daily administered to rats for five consecutive days. On day 6, ciprofloxacin was administered (10 mg/kg, i.v. and 20 mg/kg, p.o.) to rats. To assess cotreatment effect of berberine and ciprofloxacin, berberine (50 mg/kg) and ciprofloxacin (20 mg/kg) were coadministered by single oral gavage. Pharmacokinetic data were estimated by noncompartmental model. Compared with ciprofloxacin alone (control group), coadministration of berberine (50 mg/kg) and ciprofloxacin significantly decreasedCmaxof ciprofloxacin (P<0.05). In addition, the pretreatment of berberine (50 mg/kg/day) and HR (1.4 g/kg/day) significantly decreasedCmaxandAUC0→∞, compared with control group (P<0.05). The oral bioavailability of ciprofloxacin was reduced by cotreatment of berberine and pretreatment of berberine and HR. Our results suggest that the expression of P-glycoprotein and organic anion and/or organic cation transporters (OAT/OCT) could take a role in reduced oral bioavailability of ciprofloxacin by berberine and HR.
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Heemskerk, Suzanne, Alfons C. Wouterse, Frans G. M. Russel, and Rosalinde Masereeuw. "Nitric oxide down-regulates the expression of organic cation transporters (OCT) 1 and 2 in rat kidney during endotoxemia." European Journal of Pharmacology 584, no. 2-3 (April 2008): 390–97. http://dx.doi.org/10.1016/j.ejphar.2008.02.006.
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Bouchet, Stephane, Stephanie Dulucq, Karine Titier, Nicholas Moore, Mathieu Molimard, and Francois-Xavier Mahon. "Imatinib and Nilotinib Intracytoplasmic Determination Levels." Blood 114, no. 22 (November 20, 2009): 2750. http://dx.doi.org/10.1182/blood.v114.22.2750.2750.
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Abstract Abstract 2750 Poster Board II-726 Introduction Cellular uptake of imatinib is known to be mediated by Oct-1 but efflux by MDR1. In the cell, metabolism, particularly by CYP3A4, produces metabolites that could be carried by other transporters such as MRP2. Nilotinib seems to suffer less from the influence from such transporters. The aim of this study was to determine the impact of cellular exchange on the intracellular concentrations of imatinib, nilotinib or both in vitro but also among patients in order to improve the therapeutic drug monitoring of these medicines. Methods In vitro studies used the chronic myeloid leukemia cell line K562 overexpressing MDR1 (K562mdr) and wild-type K562 cells (K562wt). To investigate cellular uptake and the intra/extracellular concentration relationship, these were incubated with imatinib or nilotinib for 2h in the presence or absence of transporter inhibitors (verapamil, PSC833). Cells were precipitated by acetonitrile (with internal standards) and analysis was performed using HPLC-tandem mass spectrometry (Waters Acquity-TQD). The intracellular concentration of peripheral blood mononuclear cells (PBMC) of patients treated by these drugs was also investigated. Results In K562wt, the presence of verapamil, an inhibitor of both Oct-1 and MDR1, reduced imatinib intracellular concentration compared to the steady-state untreated K652wt, but the presence of PSC833, a specific inhibitor of MDR1, had little effect on the level of imatinib. K562mdr, that had lower steady-state imatinib cellular concentration than K562wt, recovered higher levels with verapamil but PSC833 allowed the greatest concentrations. Experiments investigating nilotinib found no difference between cell lines with or without inhibitors. Finally, the presence of both imatinib and nilotinib seemed to modify the steady-state concentration found individually. Intracellular imatinib concentration was correlated with that found in the culture medium (extracellular), but the gradient was different for each conditions for both K562wt and K562mdr, with or without inhibitors. At every concentration tested, we found the same differences in levels than in the kinetic study. Saturation was observed with imatinib, especially for untreated K562wt indicating probable involvement of active transport. Investigation of nilotinib under the same conditions did not show any difference in the gradient of each conditions and the relationship was more linear. The raw intracellular concentrations of PBMC obtained from patients (n=30) were very variable, especially for the imatinib. Correction by plasma concentration indicates individual patient's capacity for intracellular incorporation and a trend was found with response to the treatment. Conclusion Contrary to imatinib, nilotinib did not seem to be under influence of MDR1, nor of OCT1. The intracellular concentration appears as a good way to investigate pharmacokinetic resistance and could be an additional help for the management of the treatment, especially for imatinib. Disclosures: Mahon: Amgen: Honoraria; Novartis Pharma: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria.
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Nguyen, Dung N., Xiusheng Miao, Mindy Magee, Guoying Tai, Peter D. Gorycki, and Katy P. Moore. "1315. No Dose Adjustment of Metformin with Fostemsavir Coadministration Based on Mechanistic Static and Physiologically Based Pharmacokinetic Models." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S669. http://dx.doi.org/10.1093/ofid/ofaa439.1497.
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Abstract Background Fostemsavir (FTR) is an oral prodrug of the first-in-class attachment inhibitor temsavir (TMR) which is being evaluated in patients with multidrug resistant HIV-1 infection. In vitro studies indicated that TMR and its 2 major metabolites are inhibitors of organic cation transporters (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs). To assess the clinical relevance, of OCT and MATE inhibition, mechanistic static DDI prediction with calculated Imax,u/IC50 ratios was below the cut-off limits for a DDI flag based on FDA guidelines and above the cut-off limits for MATEs based on EMA guidelines. Methods Metformin is a commonly used probe substrate for OCT1, OCT2 and MATEs. To predict the potential for a drug interaction between TMR and metformin, a physiologically based pharmacokinetic (PBPK) model for TMR was developed based on its physicochemical properties, in vitro and in vivo data. The model was verified and validated through comparison with clinical data. The TMR PBPK model accurately described AUC and Cmax within 30% of the observed data for single and repeat dose studies with or without food. The SimCYP models for metformin and ritonavir were qualified using literature data before applications of DDI prediction for TMR Results TMR was simulated at steady state concentrations after repeated oral doses of FTR 600 mg twice daily which allowed assessment of the potential OCT1, OCT2, and MATEs inhibition by TMR and metabolites. No significant increase in metformin systemic exposure (AUC or Cmax) was predicted with FTR co-administration. In addition, a sensitivity analysis was conducted for either hepatic OCT1 Ki, or renal OCT2 and MATEs Ki values. The model output indicated that, a 10-fold more potent Ki value for TMR would be required to have a ~15% increase in metformin exposure Conclusion Based on mechanistic static models and PBPK modeling and simulation, the OCT1/2 and MATEs inhibition potential of TMR and its metabolites on metformin pharmacokinetics is not clinically significant. No dose adjustment of metformin is necessary when co-administered with FTR Disclosures Xiusheng Miao, PhD, GlaxoSmithKline (Employee) Mindy Magee, Doctor of Pharmacy, GlaxoSmithKline (Employee, Shareholder) Peter D. Gorycki, BEChe, MSc, PhD, GSK (Employee, Shareholder) Katy P. Moore, PharmD, RPh, ViiV Healthcare (Employee)
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Ningrum, Vitarani DA, Rochmy Istikharah, and Rheza Firmansyah. "Allele Frequency of SLC22A1 Met420del Metformin Main Transporter Encoding Gene among Javanese-Indonesian Population." Open Access Macedonian Journal of Medical Sciences 7, no. 3 (February 14, 2019): 378–83. http://dx.doi.org/10.3889/oamjms.2019.087.
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BACKGROUND: Genetic variation in the genes that encode metformin transporters has been proven to cause pharmacokinetic variability and various glycemic response to metformin. Organic Cation Transporter (OCT) 1 protein encoded by the SLC22A1 gene is primarily responsible for the process of metformin influx to the hepatocytes as the target of antihyperglycemic action as well as metformin elimination through the renal. This study aimed to determine the allele frequency distribution of the SLC22A1 Met420del gene in OCT1 among the Javanese population, the largest ethnic group in Indonesia with T2DM.
METHODS: The research involved 100 adult patients from 9 healthcare facilities in Yogyakarta Province. The PCR-RFLP method was employed as a genotype analysis to detect polymorphism using 5'-AGGTTCACGGACTCTGTGCT-3' forward primer and 5'-AAGCTGGAGTGTGCGATCT-3' reverse primer.
RESULTS: No AA variant (wild type) type was found in the SLC22A1 Met420del gene, and only 4% of the subjects had Aa heterozygote type. The allele frequencies of A and a were 2.0% and 98.0% in all subjects, respectively.
CONCLUSION: The allele frequencies in the Javanese-Indonesian population were almost the same as those in the studies involving Japanese, Chinese-Han, and Asian-American populations. This study recommends further research on the correlation between the influence of methionine deletion at codon 420 on the variability of pharmacokinetic profiles and the glycemic response to metformin as well as the incidence of gastrointestinal intolerance due to metformin administration.
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Efimova, E., A. B. Volnova, M. A. Ptuha, R. R. Gainetdinov, and M. Y. Inyushin. "P.077 Quinine- and estrogen-sensitive OCT transporters contribute to the regulation of dopamine uptake and locomotor activity in rats." European Neuropsychopharmacology 40 (November 2020): S50—S51. http://dx.doi.org/10.1016/j.euroneuro.2020.09.070.
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