title: The evaluation of CYP2B6 inhibition by artemisinin antimalarials in recombinant enzymes and human liver microsomes.
abstract: Artemisinin-based combination therapy (ACT) is the recommended treatment of uncomplicated P.falciparum malaria by the World Health Organisation (WHO). Some artemisinin compounds and anti-retroviral drugs have been shown to be metabolized by CYP2B6. In the African clinical settings, the likelihood of co-administration of ACTs and antiretroviral drugs is higher than elsewhere, posing the risk of drug-drug interactions (DDIs). This study aimed to investigate whether artemisinin compounds inhibit CYP2B6 activity in vitro using recombinant CYP2B6 (rCYP2B6) and human liver microsomes (HLM). Values for IC50 and Ki were determined by kinetic analyses using non-linear regression. In vitro to in vivo extrapolations of the likelihood of DDIs where done using a static [I]/Ki approach. Artemisinin and artemether were shown to inhibit CYP2B6 in vitro through a partial mixed type of inhibition, while dihydroartemisinin did not inhibit the enzymatic activity. IC50 values for artemisinin were 9.5 and 9.1 µM for rCYP2B6 and HLM, respectively, after 30 min of incubation. Corresponding values for artemether were 7.5 and 5.4 µM. Artemisinin did not show any time-dependency or requirement of NADPH in its mechanism, indicating a reversible mode of inhibition. Based on the [I]/Ki approach using rCYP2B6, the risk of DDIs for artemisinin was indicated to be medium to high, while artemether had a low risk. The findings indicate a potential but moderate risk of DDIs in the co-administration of artemisinin or artemether with efavirenz in the co-treatment of malaria and HIV/AIDS.
authors.affiliation: Dep. Pharmacology, Box 431, 405 30 Gothenburg, Sweden. therese.ericsson@neuro.gu.se
authors.forename: Therese
authors.initials: T
authors.lastname: Ericsson
authors.forename: Collen
authors.initials: C
authors.lastname: Masimirembwa
authors.forename: Angela
authors.initials: A
authors.lastname: Abelo
authors.forename: Michael
authors.initials: M
authors.lastname: Ashton
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D065702:Cytochrome P-450 CYP2B6; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C031327:artemisinin; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating