Differential effects of clinically used derivatives and metabolites of artemisinin in the activation of constitutive androstane receptor isoforms.

British Journal of Pharmacology
Oliver BurkM Schwab

Abstract

Widespread resistance to antimalarial drugs requires combination therapies with increasing risk of pharmacokinetic drug-drug interactions. Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding. A total of 21 selected antimalarials and 11 major metabolites were screened for binding to CAR isoforms using cellular and in vitro CAR-coactivator interaction assays, combined with in silico molecular docking. Identified ligands were further characterized by cell-based assays and primary human hepatocytes were used to elucidate induction of gene expression. Only two artemisinin derivatives arteether and artemether, the metabolite deoxyartemisinin and artemisinin itself demonstrated agonist binding to the major isoforms CAR1 and CAR3, while arteether and artemether were also inverse agonists of CAR2. Dihydroartemisinin and artesunate acted as weak inverse agonists of CAR1. While arteether showed the highest activities in vitro, it was less active than artemisinin in inducing hepatic CYP3A4 gene expression in hepatocytes. Artemisinin derivatives and metabolites differentially affect the activities of CAR isoforms and of the pregnane X recep...Continue Reading

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Citations

Mar 12, 2015·Drug Metabolism and Pharmacokinetics·Meitong ZangJie Xing
Mar 3, 2020·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Zhenyue WangJing Dong
Jun 5, 2013·Drug Metabolism and Drug Interactions·Ferdinand MolnárPaavo Honkakoski

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