The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochrome P-450 and implications for metabolic drug interactions.

Article Details

Citation

Fischer V, Johanson L, Heitz F, Tullman R, Graham E, Baldeck JP, Robinson WT

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochrome P-450 and implications for metabolic drug interactions.

Drug Metab Dispos. 1999 Mar;27(3):410-6.

PubMed ID
10064574 [ View in PubMed
]
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 apparent Km values of 0.2 to 0.7 and 7.9 to 50 microM 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 low Km 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 with Ki values of 0.3 and 0.5 microM, respectively. For CYP2C8-catalyzed 6alpha-hydroxy-paclitaxel formation the IC50 was 20 microM and for CYP1A2, CYP2C19, and CYP3A catalyzed reactions, no IC50 could be determined up to 100 microM 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 approximately 1, 2.8, and 7.1 microM 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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
FluvastatinCytochrome P450 1A1ProteinHumans
Unknown
Substrate
Inducer
Details
FluvastatinCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Details
FluvastatinCytochrome P450 2C9ProteinHumans
Unknown
Substrate
Inhibitor
Details
FluvastatinCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Details
TolbutamideCytochrome P450 2C9ProteinHumans
Unknown
Substrate
Details