Fischer V, Johanson L, Heitz F, Tullman R, Graham E, Baldeck J P, Robinson W T
Drug Metabolism and Pharmacokinetics, Novartis Institute for Biomedical Research, East Hanover, New Jersey 07936, USA.
Drug Metab Dispos. 1999 Mar;27(3):410-6.
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.
氟伐他汀是一种3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，在人肝微粒体中代谢生成5-羟基、6-羟基和N-去异丙基氟伐他汀。总代谢产物的生成呈双相性，高Km组分和低Km组分的表观Km值分别为0.2至0.7和7.9至50微摩尔，内在代谢清除率分别为1.4至4和0.3至1.5毫升/小时/毫克微粒体蛋白。几种酶，主要是CYP2C9，催化氟伐他汀的代谢。只有CYP2C9抑制剂如磺胺苯吡唑能抑制6-羟基和N-去异丙基氟伐他汀的生成。CYP2C9、CYP3A或CYP2C8的抑制剂可降低5-羟基氟伐他汀的生成。氟伐他汀反过来抑制CYP2C9催化的甲苯磺丁脲和双氯芬酸羟基化，Ki值分别为0.3和0.5微摩尔。对于CYP2C8催化的6α-羟基紫杉醇生成，IC50为20微摩尔，对于CYP1A2、CYP2C19和CYP3A催化的反应，在氟伐他汀浓度高达100微摩尔时无法测定IC50。所有三种氟伐他汀代谢产物也由重组CYP2C9生成，而CYP1A1、CYP2C8、CYP2D6和CYP3A4仅生成5-羟基氟伐他汀。CYP2C9、CYP
