Auswahl der wissenschaftlichen Literatur zum Thema „Methotrexate Toxicology“

The aim of this study was to investigate the possible protective role of caffeic acid phenethyl ester on testicular toxicity of methotrexate in rats. Nineteen male rats were divided into three groups as follows: group I, control; group II, methotrexate-treated; group III, methotrexate + caffeic acid phenethyl ester-treated. In the second day of experiment, a single dose of methotrexate was intraperitoneally administered to groups II and III, although a daily single dose of caffeic acid phenethyl ester was intraperitoneally administered to group III for 7 days. At the end of the experiment, the testes of the animals were removed and weighed. In the tissue, the level of lipid peroxidation as malondialdehyde and activities of superoxide dismutase were higher in the methotrexate group than in the control group. Lipid peroxidation levels and superoxide dismutase activities were decreased in caffeic acid phenethyl ester + methotrexate group compared with methotrexate group. The activities of catalase in the methotrexate group decreased insignificantly although its activities were significantly increased by caffeic acid phenethyl ester administration. The activity of glutathione peroxidase did not change in the groups. There was significant difference in body weight between control and methotrexate-induced groups. In conclusion, the administration of methotrexate causes elevation of oxidative stress although treatment with caffeic acid phenethyl ester has protective effects on the oxidative stress in testes.

Thymoquinone is the major active component derived from Nigella sativa. Methotrexate is a folic acid antagonist widely used in clinic. Aim of this study was to investigate the possible protective role of thymoquinone on testicular toxicity of methotrexate. Experiments were performed on male C57BL/6 mice (6 weeks old, 20 ± 2 g). The animals were divided into four groups with six mice in each group. Equivalent volumes of saline were injected intraperitoneally (i.p.) in the control group. In the thymoquinone group, mice received thymoquinone i.p. with a dose of 10 mg/kg/day for 4 days. Mice in the methotrexate group received single dose of methotrexate i.p., with a dose of 20 mg/kg. Finally, in the methotrexate plus thymoquinone group, in the first and the following 3 days after methotrexate administration, thymoquinone was injected with a dose of 10 mg/kg/day, i.p. At the end of the experiment, the left testis was quickly removed and divided into two parts for histological examination and biochemical analysis. Methotrexate alone increased total antioxidant capacity and myeloperoxidase activity compared to the controls. Thymoquinone treatment decreased total antioxidant capacity and prevented the increase in the myeloperoxidase activity. Light microscopy showed in mice that receiving methotrexate resulted in interstitial space dilatation, edema, severe disruption of the seminiferous epithelium and reduced diameter of the seminiferous tubules. Administration of thymoquinone reversed histological changes of methotrexate significantly. We suggest that thymoquinone use may decrease the destructive effects of methotrexate on testicular tissue of patients using this agent.

Indomethacin, a non-steroidal anti-inflammatory drug is known to increase the efficacy and toxicity of methotrexate, the widely used anti-cancer drug in man. The mechanism for this interaction has not been clearly established. However, since these drugs bind with albumin, a possible displacement of methotrexate by indomethacin from albumin might explain this interaction. To investigate the possible interaction an in-vitro protein-binding displacement study was carried out in 17 normal volunteers and in two groups of eight cancer patients. One group of patients had active disease and the other was in complete clinical remission. Serum samples were obtained and protein levels estimated. The protein binding of methotrexate was measured alone and with indomethacin using equilibrium dialysis. Statistical analysis of results suggested that the binding of methotrexate is not influenced by indomethacin, confirming that methotrexate is not displaced by indomethacin.

Le MTX est un agent anticancéreux utilisé à hautes doses pour le traitement des hémopathies malignes et de certaines tumeurs solides. Il présente une importante variabilité pharmacocinétique (PK) traduite par des surexpositions à l'origine de toxicités très sévères, surtout lors d'une administration à haute dose. Les retards d'élimination du MTX surviennent encore de manière inattendue et il n'existe à ce jour aucun biomarqueur qui permette un diagnostic précoce du risque de surexposition. Nos travaux ont focalisé sur les déterminants de l'élimination rénale du MTX, et en particulier le rôle du transporteur MRP2/ABCC2 dans ce processus. Ce travail s'inscrit donc (1) dans la recherche de biomarqueurs métabolomiques urinaires prédictifs de la PK du MTX et (2) dans l'identification de substrats endogènes de MRP2 parmi un panel de 217 acides organiques urinaires analysés par chromatographie gazeuse couplée à la spectrométrie de masse. Nos analyses ont abouti à un profil de 28 anions organiques endogènes, prédictifs de la CL MTX. L'outil était en revanche mal adapté à la prédiction des retards d'élimination. Pour la 2eme partie, nos résultats tendent à montrer que 8 métabolites urinaires sont des bio-marqueurs potentiels de l'activité de MRP2. Leur utilisation en clinique nécessite encore des études confirmatoires
MTX is an anticancer agent used at high doses for the treatment of malignant haemopathies and some solid tumors. It presents an important pharmacokinetic variability (PK), manifested by overexposures causing very severe toxicities, especially when administered at high doses. Delayed elimination of MTX still occurs unexpectedly and there is currently no biomarker that allows early diagnosis of the risk of overexposure. Our work focused on the determinants of renal elimination of MTX, and particularly on the role of MRP2 / ABCC2 in this process. This work is therefore devoted to (1) the search for metabolomic biomarkers predictive of MTX PK and (2) the identification of endogenous substrates of MRP2, from a panel of 217 urinary organic acids analyzed by gas chromatography-mass spectrometry. Our analyses resulted in a profile of 28 endogenous organic anions, predictive of CL MTX. The tool was, on the other hand, poorly adapted to the prediction of delayed elimination. For the second part, our results tend to show that 8 urinary metabolites are potential biomarkers of MRP2 activity. Their clinical use still requires confirmatory studies

El metotrexato (MTX) es el fármaco de elección en primera línea de tratamiento para pacientes con artritis reumatoide. En las últimas décadas ha habido un gran interés para identificar marcadores biológicos que puedan predecir con exactitud y fiabilidad la eficacia y toxicidad del MTX. Los polimorfismos (SNPs, Single Nucleotide Polymorphism) en los genes que participan de forma directa o indirecta en la vía metabólica del MTX y en su transporte y activación (poliglutamación) celular, pueden ser predictores de respuesta y toxicidad del MTX. El objetivo del trabajo es valorar la utilidad de diferentes marcadores farmacogenéticos en relación a la respuesta y/o toxicidad de pacientes con artritis reumatoide tratados con MTX en monoterapia. El trabajo se ha dividido en dos partes: La primera parte se basa en el estudio de 27 polimorfismos de genes que tienen que ver con el mecanismo de acción del MTX (DHFR, TYMS, MTHFR, ATIC y CCND1) y, la segunda, en el estudio de 34 polimorfismos de genes que participan en el transporte celular del MTX y en su activación e inactivación través de la poliglutamación (SLC19A1 / RFC1, ABCB1, FPGS y GGH). En relación a los genes que participan en el mecanismo de acción del MTX los resultados muestran una asociación entre dos SNPs en el gen MTHFR, rs17421511 y rs1476413, y uno en el gen DHFR, rs1643650, y la respuesta al tratamiento con MTX en pacientes con artritis reumatoide. Asimismo, también se ha encontrado que dos SNPs en el gen ATIC, rs16853826 y rs10197559, se asocian con toxicidad. En relación a los genes que participan en el transporte celular del MTX y en su activación e inactivación a través de la poliglutamación los resultados obtenidos en este trabajo muestran una asociación entre dos SNPs en el gen FPGS, rs10987742 y rs10106, y la respuesta al tratamiento con MTX. El SNP rs10106 también está asociado con la presencia de eventos adversos y el tiempo de supervivencia del fármaco. Los resultados también muestran que tres SNPs en el gen ABCB1, rs868755, rs10280623 y rs1858923, están asociados con la toxicidad al MTX, y que dos de los SNPs del mismo gen, rs10264990 y rs868755, también se asocian con el tiempo de supervivencia del MTX. En conclusión, determinadas variantes genéticas en los genes que participan en la vía metabólica del MTX y en su transporte y activación celular, podrían ser consideradas como marcadores farmacogenéticos de respuesta y toxicidad en pacientes con artritis reumatoide tratados con MTX en monoterapia.
Methotrexate (MTX) is the first-line treatment option for rheumatoid arthritis (RA) patients. Recently, the interest of identifying biomarkers that can predict the efficacy and toxicity of MTX has been grown. Polymorphisms (SNPs, Single Nucleotide Polymorphism) in genes involved directly or indirectly in the metabolic pathway of MTX and in the transport and activation (polyglutamation) of MTX inside the cell can be predictors of response and toxicity of MTX. The objective of this study is to evaluate the usefulness of different pharmacogenetics markers in relation to the response and / or toxicity of rheumatoid arthritis patients treated with MTX in monotherapy. The investigation has been divided into two parts. The first part is based on the study of 27 polymorphisms of 5 genes that are involved with the mechanism of action of MTX (DHFR, TYMS, MTHFR, ATIC and CCND1). The second part is based on the study of 34 polymorphisms of 4 genes involved in the cellular transport of MTX and in its activation and inactivation through polyglutamation (SLC19A1 / RFC1, ABCB1, FPGS and GGH). Regarding genes involved in the mechanism of MTX’ action the results show an association between three SNPs and the response to treatment with MTX in patients with rheumatoid arthritis. The involved SNPs are rs17421511 and rs1476413 of MTHFR gene and the SNP rs1643650 of the DHFR gene. Besides, the two SNPs rs16853826 and rs10197559 of ATIC gene are associated with toxicity. Concerning genes involved in cellular transport of MTX and in their activation/inactivation through polyglutamation the results obtained in this study show an association between two SNPs and the treatment response of MTX. In this case, the involved SNPs are rs10987742 and rs10106 of FPGS gene. The SNP rs10106 is also associated with the presence of adverse events and the survival time of the drug. The results also show that three SNPs rs868755, rs10280623 and rs1858923 of ABCB1 gene are associated with MTX toxicity; and two SNPs rs868755 and rs10264990 of the same gene are also associated with the survival time of MTX. In conclusion, certain genetic variants in genes involved in the metabolic pathway of MTX and in its transportation and cellular activation could be considered as pharmacogenetics markers for response and toxicity in rheumatoid arthritis’ patients treated with MTX in monotherapy.