Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies.
Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies.
复制标题
DOI：
--
复制
发表时间：
1996-04
期刊：
影响因子：
--
通讯作者：
D. Black;K. Kunze;L. Wienkers;B. Gidal;T. Seaton;N. Mcdonnell;J. Evans;J. Bauwens;William F. Trager
中科院分区：
文献类型：
--
作者：
D. Black;K. Kunze;L. Wienkers;B. Gidal;T. Seaton;N. Mcdonnell;J. Evans;J. Bauwens;William F. Trager
与基于人体外微粒体实验的预期一致，6名志愿者连续6天给予氟康唑（400 mg/天）显著降低了华法林对映体的细胞色素P450（P450）依赖性代谢清除率。特别是，P4502 C9催化（S）-华法林的6-和7-羟基化，主要负责终止华法林的抗凝作用的途径，被抑制约70%。氟康唑引起的（S）-华法林药代动力学变化显著增加了华法林的低凝血酶原血症效应的幅度和持续时间。这些观察结果表明，氟康唑和华法林联合给药将导致具有临床意义的基于代谢的相互作用。氟康唑也强烈抑制了（R）-华法林清除的主要P450依赖性体内途径。10-羟基化（一种仅由P4503 A4催化的代谢途径）被抑制45%，而6-、7-和8-羟基化分别被抑制61%、73%和88%。酚类代谢物的强效抑制表明，P4501 A2以外的酶（在体外受到氟康唑的微弱抑制）主要负责这些代谢物在体内的形成，如体外动力学研究所预测的。这些数据表明，氟康唑可以预期与任何药物相互作用，其清除率主要是由P450 2C 9，3A 4，和其他尚未确定的亚型。总体而言，结果强烈支持以下假设：基于代谢的体内药物相互作用可以从人体外微粒体数据中预测。
Consistent with expectations based on human in vitro microsomal experiments, administration of fluconazole (400 mg/day) for 6 days to six human volunteers significantly reduced the cytochrome P450 (P450)-dependent metabolic clearance of the warfarin enantiomers. In particular, P4502C9 catalyzed 6- and 7-hydroxylation of (S)-warfarin, the pathway primarily responsible for termination of warfarin's anticoagulant effect, was inhibited by approximately 70%. The change in (S)-warfarin pharmacokinetics caused by fluconazole dramatically increased the magnitude and duration of warfarin's hypoprothrombinemic effect. These observations indicate that co-administration of fluconazole and warfarin will result in a clinically significant metabolically based interaction The major P450-dependent, in vivo pathways of (R)-warfarin clearance were also strongly inhibited by fluconazole. 10-Hydroxylation, a metabolic pathway catalyzed exclusively by P4503A4, was inhibited by 45% whereas 6-, 7-, and 8-hydroxylations were inhibited by 61, 73, and 88%, respectively. The potent inhibition of the phenolic metabolites suggests that enzymes other than P4501A2 (weakly inhibited by fluconazole in vitro) are primarily responsible for the formation of these metabolites in vivo as predicted from in vitro kinetic studies. These data suggest that fluconazole can be expected to interact with any drug whose clearance is dominated by P450s 2C9, 3A4, and other as yet undefined isoforms. Overall, the results strongly support the hypothesis that metabolically based in vivo drug interactions may be predicted from human in vitro microsomal data.