Transon C, Leemann T, Vogt N, Dayer P
Division of Clinical Pharmacology, University Hospital, Geneva, Switzerland.
Clin Pharmacol Ther. 1995 Oct;58(4):412-7. doi: 10.1016/0009-9236(95)90054-3.
(+/-)-Fluvastatin is a synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that selectively and competitively inhibits P450TB (CYP2C9) in vitro. The potential for kinetic interactions in vivo between fluvastatin and P450TB substrates was therefore investigated in healthy volunteers.
Diclofenac (25 mg orally) oxidation was used as a marker of P450TB activity on days 0, 1, and 8 of fluvastatin treatment (40 mg/day).
Diclofenac peak concentration (Cmax) increased over time (0.28 [SD, 0.12], 0.38 [0.20], and 0.45 [0.4] mg/L on days 0, 1, and 8, respectively). Oral clearance was reduced on days 1 and 8 (14% and 15%, respectively). A time-dependent decrease in urinary metabolic ratio (MR, 4'-hydroxydiclofenac/diclofenac) was noted (1.07 [0.34], 0.90 [0.23] and 0.70 [0.18] on days 0, 1, and 8, respectively [p < 0.0001]) for the first 4 hours. The interaction was clear in only some individuals; MR reduction was related to baseline MR and it was more pronounced in subjects with a higher baseline MR (p < 0.01). Fluvastatin Cmax (0.18 [0.11] and 0.32 [0.1] mg/L on days 1 and 8, respectively) and area under the curve (0.28 [0.12] and 0.43 [0.15] hr.mg/L on days 1 and 8, respectively; p < 0.001) increased over time. Diclofenac MR reduction was correlated with fluvastatin concentrations.
Interactions between fluvastatin and P450TB substrates (phenytoin, oral anticoagulants, oral hypoglycemic agents, and nonsteroidal antiinflammatory drugs) may occur, at least in some patients.
（±）-氟伐他汀是一种合成的3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，在体外可选择性且竞争性地抑制P450TB（CYP2C9）。因此，在健康志愿者中研究了氟伐他汀与P450TB底物在体内发生动力学相互作用的可能性。
在氟伐他汀治疗（40mg/天）的第0、1和8天，使用双氯芬酸（口服25mg）氧化作为P450TB活性的标志物。
双氯芬酸的峰浓度（Cmax）随时间增加（第0、1和8天分别为0.28[标准差，0.12]、0.38[0.20]和0.45[0.4]mg/L）。第1天和第8天口服清除率降低（分别为14%和15%）。在最初4小时内，观察到尿代谢率（MR，4'-羟基双氯芬酸/双氯芬酸）随时间下降（第0、1和8天分别为1.07[0.34]、0.90[0.23]和0.70[0.18][p<0.0001]）。这种相互作用仅在部分个体中明显；MR降低与基线MR相关，在基线MR较高的受试者中更明显（p<0.01）。氟伐他汀的Cmax（第1天和第8天分别为0.18[0.11]和0.32[0.1]mg/L）和曲线下面积（第1天和第8天分别为0.28[0.12]和0.43[0.15]hr·mg/L；p<0.001）随时间增加。双氯芬酸MR降低与氟伐他汀浓度相关。
至少在部分患者中，氟伐他汀与P450TB底物（苯妥英、口服抗凝剂、口服降糖药和非甾体抗炎药）之间可能发生相互作用。
