title: Effects of artemisinin antimalarials on Cytochrome P450 enzymes in vitro using recombinant enzymes and human liver microsomes: potential implications for combination therapies.
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.
authors.affiliation: Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at the University of Gothenburg , Gothenburg , Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Ericsson
authors.forename: Jesper
authors.initials: J
authors.lastname: Sundell
authors.forename: Angelica
authors.initials: A
authors.lastname: Torkelsson
authors.forename: Kurt-Jürgen
authors.initials: KJ
authors.lastname: Hoffmann
authors.forename: Michael
authors.initials: M
authors.lastname: Ashton
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D000077549:Artemether; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D065607:Cytochrome P-450 Enzyme Inhibitors; D011994:Recombinant Proteins; D000077332:Artesunate; C039060:artenimol; D003577:Cytochrome P-450 Enzyme System; C031327:artemisinin; D000077549:Artemether; C504573:CYP1A2 protein, human; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19
keywords: Artemether; CYP enzymes; artesunate; dihydroartemisinin; drug–drug interactions; inhibition