TY - JOUR T1 - The 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor Fluvastatin: Effect on Human Cytochrome P-450 and Implications for Metabolic Drug Interactions JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 410 LP - 416 VL - 27 IS - 3 AU - Volker Fischer AU - Laurie Johanson AU - Francis Heitz AU - Robert Tullman AU - Elizabeth Graham AU - Jean-Pierre Baldeck AU - William T. Robinson Y1 - 1999/03/01 UR - http://dmd.aspetjournals.org/content/27/3/410.abstract N2 - Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, was metabolized by human liver microsomes to 5-hydroxy-, 6-hydroxy-, and N-deisopropyl-fluvastatin. Total metabolite formation was biphasic with apparentKm values of 0.2 to 0.7 and 7.9 to 50 μM and intrinsic metabolic clearance rates of 1.4 to 4 and 0.3 to 1.5 ml/h/mg microsomal protein for the high and lowKm components, respectively. Several enzymes, but mainly CYP2C9, catalyzed fluvastatin metabolism. Only CYP2C9 inhibitors such as sulfaphenazole inhibited the formation of both 6-hydroxy- and N-deisopropyl-fluvastatin. 5-Hydroxy-fluvastatin formation was reduced by compounds that are inhibitors of CYP2C9, CYP3A, or CYP2C8. Fluvastatin in turn inhibited CYP2C9-catalyzed tolbutamide and diclofenac hydroxylation withKi values of 0.3 and 0.5 μM, respectively. For CYP2C8-catalyzed 6α-hydroxy-paclitaxel formation the IC50 was 20 μM and for CYP1A2, CYP2C19, and CYP3A catalyzed reactions, no IC50 could be determined up to 100 μM fluvastatin. All three fluvastatin metabolites were also formed by recombinant CYP2C9, whereas CYP1A1, CYP2C8, CYP2D6, and CYP3A4 produced only 5-hydroxy-fluvastatin. Km values were ∼1, 2.8, and 7.1 μM for CYP2C9, CYP2C8, and CYP3A, respectively. No difference in fluvastatin metabolism was found between the CYP2C9R144 and CYP2C9C144 alleles, suggesting the absence of polymorphic fluvastatin metabolism by these alleles. CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2E1, and CYP3A5 did not produce detectable amounts of any metabolite. This data indicates that several human cytochrome P-450 enzymes metabolize fluvastatin with CYP2C9 contributing 50–80%. Any coadministered drug would therefore only partially reduce the metabolic clearance of fluvastatin; therefore, the likelihood for serious metabolic drug interactions is expected to be minimal. The American Society for Pharmacology and Experimental Therapeutics ER -