Abstract
Fluvastatin (F) is a racemic mixture of 2 enantiomers (3S,5R & 3R,5S). F is a potent CYP2C9 inhibitor in vitro. We studied the effect of F on CYP2C9 using warfarin (W) as a probe. A randomized, 2-treatment crossover study was conducted in 20 healthy Caucasian adults (10 M, 10 premenopausal F) with a 21 d washout between phases. Ten smokers & 10 nonsmokers received single dose W 10mg + vitamin K (K) 10mg (W alone) or single dose W + K after F 40mg twice daily for 14 d (W inhibition). All subjects were genotype CYP2C9*1/*1 or *1/*2. Plasma concentrations of 3S,5R- & 3R,5S-F were obtained with W administration on Day 14 using HPLC. Blood samples for W were obtained over 5 d during each phase. Extent of CYP2C9 inhibition was measured by comparing the ratio of S-W AUC during W inhibition to W alone. (See Table) Clinical Pharmacology & Therapeutics (2004) 75, P28–P28; doi: 10.1016/j.clpt.2003.11.106 Table 1. Linear regression analyses show significant, but weak correlations between Cat 1 hr or 3S,5R-F AUC and extent of W inhibition. For 3R,5S-F, a weak correlation was found between Cat 1 hr and extent of W inhibition. These findings suggest that in vivo F is a weak inhibitor of CYP2C9. W alone (range) W inhibition (range) Ratio of W inhibition: W alone 3R,5S-F (range) 3S,5R-F (range) S-W AUC (ug*hr/mL) S-W AUC (ug*hr/mL) Extent of Inhibition (S-W AUC) Cat 1hr(ng/mL) AUC (ng*hr/mL) Cat 1hr(ng/mL) AUC (ng*hr/mL) 15.4±4.2 (8.8–26.9) 19.9±7.2 (12.3–36.6) 1.3±0.3 (0.9–1.8) 109±73 (3–247) 272±195 (59–570) 185±127 (19–473) 558±252 (200–1149) Linear Regressions r2=0.28 r2=0.14 r2=0.31 r2=0.25 p=0.02 p=NS p=0.02 p=0.04
Published Version
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