The contribution of the enzymes CYP2D6 and CYP2C19 in the demethylation of artemether in healthy subjects.
The contribution of the enzymes CYP2D6 and CYP2C19 to the metabolism of artemether was evaluated in a cross-over study in seven healthy adult Caucasian subjects. The pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin were compared when given 100 mg artemether orally alone or in combination with either CYP2D6-inhibitor quinidine or CYP2C19-inhibitor omeprazole. Plasma concentrations of artemether and dihydroartemisinin were measured with reversed phase high performance liquid chromatography with electro-chemical detection (HPLC-ED). Artemether was rapidly absorbed with a mean tmax of 0.8 h (95% confidence interval, CI=0.5-1.1) reaching a mean Cmax of 29 ng/ml (14-45 ng/ml). The mean elimination half-life was 1.3 h (0.8-1.8 h). The pharmacokinetic parameters for dihydroartemisinin were not significantly different from those for artemether. Artemether combined with quinidine revealed no significant changes in the plasma concentrations of either artemether or dihydroartemisinin. No changes were seen in the combination with omeprazole as a CYP2C19 inhibitor. A second peak in the plasma concentration profile was observed 2-4 h after drug intake. This phenomenon was possibly related to variable gastric emptying. No major contribution of the enzymes CYP2D6 or CYP2C19 was found in artemether metabolism. No interethnic differences in artemether metabolism on the basis of a genetic polymorphism of these enzymes is to be expected.
van Agtmael
M A
MA
Department of Clinical Pharmacology and Pharmacotherapy, Academic Medical Centre, Amsterdam, The Netherlands.
Van Der Graaf
C A
CA
Dien
T K
TK
Koopmans
R P
RP
van Boxtel
C J
CJ
D000284:Administration, Oral; D000328:Adult; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D000962:Antimalarials / Q000378:metabolism* / Q000493:pharmacokinetics; D019540:Area Under Curve; D000077549:Artemether; D037621:Artemisinins; D001189:Aryl Hydrocarbon Hydroxylases; D001682:Biological Availability; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D008297:Male; D008745:Methylation; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009853:Omeprazole / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D012717:Sesquiterpenes / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics
D000897:Anti-Ulcer Agents; D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C039060:artenimol; D003577:Cytochrome P-450 Enzyme System; D000077549:Artemether; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine; D009853:Omeprazole