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Effects of artemisinin antimalarials on Cytochrome P450 enzymes in vitro using recombinant enzymes and human liver microsomes: potential implications for combination therapies.

Journal article
Authors Therese Ericsson
Jesper Sundell
Angelica Torkelsson
Kurt-Jürgen Hoffmann
Michael Ashton
Published in Xenobiotica
Volume 44
Issue 7
Pages 615-626
ISSN 0049-8254
Publication year 2014
Published at Institute of Neuroscience and Physiology, Department of Pharmacology
Pages 615-626
Language en
Links dx.doi.org/10.3109/00498254.2013.87...
Keywords Artemether, artesunate, CYP enzymes, dihydroartemisinin, drug–drug interactions, inhibition
Subject categories Other Medical Sciences

Abstract

1. Cytochrome P450 enzyme system is the most important contributor to oxidative metabolism of drugs. Modification, and more specifically inhibition, of this system is an important determinant of several drug–drug interactions (DDIs). 2. Effects of the antimalarial agent artemisinin and its structural analogues, artemether, artesunate and dihydroartemisinin, on seven of the major human liver CYP isoforms (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4) were evaluated using recombinant enzymes (fluorometric assay) and human liver microsomes (LC–MS/MS analysis). Inhibitory potency (IC50) and mechanisms of inhibition were evaluated using nonlinear regression analysis. In vitro–in vivo extrapolation using the [I]/Ki ratio was applied to predict the risk of DDI in vivo. 3. All compounds tested inhibited the enzymatic activity of CYPs, mostly through a mixed type of inhibition, with CYP1A2, 2B6, 2C19 and 3A4 being affected. A high risk of interaction in vivo was predicted if artemisinin is coadministrated with CYP1A2 or 2C19 substrates. 4. With respect to CYP1A2 inhibition in vivo by artemisinin compounds, our findings are in line with previously published data. However, reported risks of interaction may be overpredicted and should be interpreted with caution.

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