Effects of fluvastatin and cigarette smoking on CYP2C9 activity measured using the probe S-warfarin

Abstract

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. 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. 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. 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.