Abstract

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 apparentK_m 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 lowK_m 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 withK_i 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. K_m values were ∼1, 2.8, and 7.1 μM for CYP2C9, CYP2C8, and CYP3A, respectively. No difference in fluvastatin metabolism was found between the CYP2C9_R144 and CYP2C9_C144 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.