Role of cytochrome P450-mediated metabolism and involvement of reactive metabolite formations on antiepileptic drug-induced liver injuries

The Journal of Toxicological Sciences
Eita Sasaki, Tsuyoshi Yokoi

Abstract

Several drugs have been withdrawn from the market or restricted to avoid unexpected adverse outcomes. Drug-induced liver injury (DILI) is a serious issue for drug development. Among DILIs, idiosyncratic DILIs have been a serious problem in drug development and clinical uses. Idiosyncratic DILI is most often unrelated to pharmacological effects or the dosing amount of a drug. The number of drugs that cause idiosyncratic DILI continue to grow in part because no practical preclinical tests have emerged that can identify drug candidates with the potential for developing idiosyncratic DILIs. Nevertheless, the implications of drug metabolism-related factors and immune-related factors on idiosyncratic DILIs has not been fully clarified because this toxicity can not be reproduced in animals. Therefore, accumulated evidence for the mechanisms of the idiosyncratic toxicity has been limited to only in vitro studies. This review describes current knowledge of the effects of cytochrome P450 (CYP)-mediated metabolism and its detoxification abilities based on studies of idiosyncratic DILI animal models developed recently. This review also focused on antiepileptic drugs, phenytoin (diphenyl hydantoin, DPH) and carbamazepine (CBZ), which have r...Continue Reading

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Citations

Jul 16, 2020·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Joseph GeorgeMikihiro Tsutsumi
Sep 4, 2020·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Tsuyoshi Yokoi
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Sep 26, 2020·Annual Review of Pharmacology and Toxicology·Tsuyoshi Yokoi, Shingo Oda
Oct 15, 2020·International Journal of Molecular Sciences·Dmitry A FilimonovVladimir V Poroikov
Apr 7, 2021·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Kosuke HaradaTadahiro Shinozawa

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