Artemisinin induces omeprazole metabolism in human beings.
OBJECTIVE
This study investigated whether time-dependent artemisinin pharmacokinetics correlated to CYP3A4 or CYP2C19 activity in vivo.


METHODS
Artemisinin (two oral doses per day of 250 mg) was given to nine healthy Vietnamese subjects for 7 days (day 1 to day 7). Single 20 mg doses of omeprazole were given orally on day -7, day 1, and day 7. Single doses of artemisinin and omeprazole were given in combination on day 14 after a 6-day washout period. The pharmacokinetics of artemisinin, omeprazole, hydroxyomeprazole, and omeprazole sulfone were evaluated on days -7, 1, 7, and 14. On the same days urine was collected for the determination of 6beta-hydroxycortisol and cortisol excretion.


RESULTS
Areas under plasma concentration-time curves (AUC) for artemisinin and omeprazole decreased on day 7 to 20% (95% confidence intervals, 13%, 28%) and 35% (25%, 46%), respectively, compared with values on day 1. AUC ratios for hydroxyomeprazole/omeprazole increased 2.2-fold (1.7, 2.7) on day 7 compared with values on day 1. All values were normalized at day 14. There were no significant changes in the omeprazole sulfone/omeprazole ratio or in the 6beta-hydroxycortisol/cortisol ratio between the study days. In one subject found to have poor CYP2C19 metabolization, the elimination of omeprazole increased after artemisinin exposure, with no change in the hydroxyomeprazole/omeprazole AUC ratio.


CONCLUSIONS
Artemisinin did not alter CYP3A4 activity, whereas an increase in CYP2C19 activity was observed. The increased elimination of omeprazole in both poor and extensive CYP2C19 metabolizers suggests artemisinin induces both CYP2C19 and another enzyme.
Svensson
U S
US
Department of Pharmacy, Uppsala University, Sweden.
Ashton
M
M
Trinh
N H
NH
Bertilsson
L
L
Dinh
X H
XH
Nguyen
V H
VH
Nguyen
T N
TN
Nguyen
D S
DS
Lykkesfeldt
J
J
Le
D C
DC
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000328:Adult; D000962:Antimalarials / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D019540:Area Under Curve; D037621:Artemisinins; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009853:Omeprazole / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D012016:Reference Values; D012717:Sesquiterpenes / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D013997:Time Factors
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000962:Antimalarials; D037621:Artemisinins; D004791:Enzyme Inhibitors; D012717:Sesquiterpenes; C040450:omeprazole sulfone; D003577:Cytochrome P-450 Enzyme System; C049963:5-hydroxymethylomeprazole; C031327:artemisinin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009853:Omeprazole