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

ABSTRACT:

Background and purpose

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.

Experimental approach

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.

Key results

Only two artemisinin derivatives arteether and artemether, the met

SUBMITTER: Burk O 

PROVIDER: S-EPMC3449269 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature