Artemisinin and CYP2A6 activity in healthy subjects.
OBJECTIVE
To investigate whether the antimalarial drug artemisinin affects CYP2A6 activity in healthy subjects and to compare the utility of coumarin and nicotine as in vivo probe compounds for CYP2A6.


METHODS
Twelve healthy male Vietnamese subjects were given coumarin or nicotine in randomized sequence before and after 5 days of a repeated oral administration of artemisinin during two different treatment periods 1 month apart. Sequential blood samples were drawn at baseline 7 days prior to artemisinin treatment and on the first and fifth day of artemisinin treatment during both treatment periods. Plasma concentrations of 7-hydroxycoumarin glucuronide (7-OHCG), nicotine, cotinine and artemisinin were analysed by high-performance liquid chromatography and those of coumarin and 7-hydroxycoumarin (7-OHC) were determined by liquid chromatography-tandem mass spectrometry. Urine, collected in two time intervals on the days of coumarin intake, was treated with beta-glucuronidase and analysed for 7-OHC levels.


RESULTS
Artemisinin AUC(0-infinity) values decreased significantly to 23% [95% confidence interval (CI) 18%-28%] on the fifth day of artemisinin administration as compared with the first. The sum of renally excreted 7-OHC and 7-OHCG increased by 1.55-fold (adjusted 95% CI 1.08-2.23) in the 3- to 8-h interval compared to baseline 7 days before. The 7-OHCG/7-OHC plasma AUC(0-infinity) ratio increased by 1.72-fold (adjusted 95% CI 1.16-2.54) following 5 days of artemisinin intake. There was no significant change in the cotinine/nicotine AUC(0-11 hr) ratio between study days.


CONCLUSIONS
Artemisinin significantly increased the sum of renally excreted 7-OHC and 7-OHCG in one of the two collection intervals, suggesting an induction of CYP2A6. A significant increase in the 7-OHCG to 7-OHC AUC(0-infinity) ratio indicates artemisinin to be an inducer of glucuronidation.
Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at Göteborg University, P.O. Box 431, 405 30, Göteborg, Sweden.
Sara
S
Asimus
Trinh Ngoc
TN
Hai
Nguyen
N
Van Huong
Michael
M
Ashton
D000328:Adult; D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D037621:Artemisinins / Q000493:pharmacokinetics / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D003374:Coumarins / Q000008:administration & dosage / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D065637:Cytochrome P-450 CYP2A6; D004790:Enzyme Induction / Q000187:drug effects*; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage / Q000493:pharmacokinetics; D053719:Tandem Mass Spectrometry; D014468:Umbelliferones / Q000097:blood; D014744:Vietnam
D000962:Antimalarials; D037621:Artemisinins; D003374:Coumarins; D014468:Umbelliferones; C031477:7-hydroxycoumarin; C039928:7-hydroxycoumarin glucuronide; D009538:Nicotine; C031327:artemisinin; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6