Effects of fluvastatin and cigarette smoking on CYP2C9 activity measured using the probe S-warfarin.
OBJECTIVE
The effect of cigarette smoking on CYP2C9 activity is unknown. We conducted a study to evaluate whether there is a difference in CYP2C9 activity in smokers versus non-smokers by examining S-warfarin AUC after CYP2C9 inhibition with fluvastatin. In addition, the effect of the CYP2C9 inhibitor fluvastatin was evaluated using S-warfarin as a probe.


METHODS
A randomized, single dose, two-treatment crossover study of warfarin with a washout period of 21 days was performed. Eighteen healthy Caucasian smokers and non-smokers, genotyped as CYP2C9*1/*1 or CYP2C9*1/*2, received warfarin 10 mg plus vitamin K 10 mg to measure baseline CYP2C9 activity. Warfarin dosing was repeated after 18 days of fluvastatin 40 mg twice daily to evaluate CYP2C9 activity after inhibition.


RESULTS
The S-warfarin AUC(0-infinity) between smokers and non-smokers did not differ by >25% after inhibition. There was no difference in S-warfarin AUC(0-infinity) during baseline (p = 0.45) or inhibition (p = 0.19) periods for smokers versus non-smokers. Fluvastatin increased the AUC of S-warfarin by 42+/-29% and 26+/-18% in smokers and nonsmokers, respectively. Linear regression analyses showed significant but weak correlations between peak concentrations (C(at 1 h)) or (-) 3S,5R-fluvastatin AUC(0-12 h) and extent of warfarin inhibition. For (+) 3R,5S-fluvastatin, a weak correlation was found between C(at 1 h) and extent of warfarin inhibition.


CONCLUSIONS
Cigarette smoking does not affect CYP2C9 activity as evaluated using S-warfarin as a CYP2C9 probe. Fluvastatin is a weak inhibitor of CYP2C9 activity in both smokers and non-smokers.
Kim
Myong-Jin
MJ
Clinical Pharmacology Research Center, Bassett Healthcare, One Atwell Road, Cooperstown, NY 13326-1394, USA.
Nafziger
Anne N
AN
Kashuba
Angela D M
AD
Kirchheiner
Julia
J
Bauer
Steffen
S
Gaedigk
Andrea
A
Bertino
Joseph S
JS
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D012907:Smoking / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D014859:Warfarin / Q000097:blood / Q000737:chemistry
D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D000077340:Fluvastatin; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases