Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (−)-3s,5r-fluvastatin and (+)-3r,5s-fluvastatin in healthy volunteers

Introduction In vitro data indicate that biotransformation of the synthetic 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitor fluvastatin is catalyzed by the cytochrome P450 (CYP) enzyme 2C9. The consequences of CYP2C9 genetic polymorphisms on fluvastatin pharmacokinetics and on its efficacy have not been investigated in humans thus far. Methods Twenty-four healthy heterozygous or homozygous carriers of the CYP2C9 variants Arg144Cys (*2) and Ile359Leu (*3) and 2 individuals with the deficient CYP2D6 genotype *4/*4 took 40 mg racemic fluvastatin daily for 14 days. All subjects had also been genotyped for CYP2C8, CYP2C19, and CYP2D6 polymorphisms. Pharmacokinetics was analyzed after the first fluvastatin administration. Serum lipid concentrations were measured before fluvastatin intake and on day 15. Plasma concentrations of (+)-3R,5S-fluvastatin and of (−)-3S,5R-fluvastatin were quantified by enantiospecific HPLC. Results Pharmacokinetics of both enantiomers showed statistically significant differences according to the number of CYP2C9*3 alleles (P < .0001, F test). Mean (and SD) values for area under the curve of the active (+)-3R,5S-fluvastatin in carriers of the genotype CYP2C9*1/*1, *1/*3, and *3/*3 were 173 (85) μg · L−1 · h, 231 (85) μg · L−1 · h, and 533 (120) μg · L−1 · h, respectively. The corresponding values for area under the curve of (−)-3S,5R-fluvastatin were 227 (133) μg · L−1 · h, 360 (103) μg · L−1 · h, and 1126 (311) μg · L−1 · h for CYP2C9*1/*1, *1/*3, and *3/*3, respectively. The CYP2C9*2 variant did not have any significant influence on fluvastatin kinetics, nor did the CYP2C8*3 allele, which was tightly linked with CYP2C9*2. Total serum cholesterol and low-density lipoprotein cholesterol concentrations decreased significantly during the 14-day treatment period (P < .001), but no correlation with the CYP2C9 genotype was found. Conclusions The pharmacokinetics of both enantiomers of fluvastatin depended on the CYP2C9 genotype, with a 3-fold group mean difference in the active enantiomer and even greater differences in the inactive enantiomer, but differences in plasma concentrations were not reflected in cholesterol lowering after 14 days of fluvastatin intake in healthy volunteers. Clinical Pharmacology doi: 10.1016/S0009-9236(03)00121-8