Warfarin-fluconazole. I. Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: in vitro studies.
Warfarin-fluconazole. I. Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: in vitro studies.
复制标题
DOI：
--
复制
发表时间：
1996-04
期刊：
影响因子：
--
通讯作者：
K. Kunze;L. Wienkers;K. Thummel;W. Trager
中科院分区：
文献类型：
--
作者：
K. Kunze;L. Wienkers;K. Thummel;W. Trager
抗真菌药物氟康唑被发现是细胞色素P450 (P450) 2C9 （Ki = 7-8微米）的有效抑制剂，细胞色素P450 (P450) 2C9是在体内清除活性较强的抗凝剂(S)-华法林(S)-7-和(S)-6-羟基华法林代谢产物（85%）的主要酶。氟康唑还被发现是p4503a4催化的(R)-10-羟基华法林（Ki = 15-18微米）形成的有效抑制剂，以及负责(R)-6-, (R)-7-和(R)-8-羟基华法林（Ki = 2-6微米）形成的低KM P450酶。相比之下，用P4501A2抑制剂furafylline和表达dna的P4501A2进行的实验表明，氟康唑是该酶的弱抑制剂（Ki > 800微米），氟康唑不能显著抑制P4501A2依赖性的(R)-华法林的6-羟基化。从这些研究中得出的预测，氟康唑是华法林体内代谢的有效抑制剂，在附带文章“华法林-氟康唑II”中报道的补充研究中得到了验证。
The antifungal agent fluconazole was found to be a potent inhibitor of cytochrome P450 (P450) 2C9 (Ki = 7-8 microM), the principal enzyme responsible for the clearance (85%) of the more potent anticoagulant (S)-warfarin to the inactive (S)-7- and (S)-6-hydroxywarfarin metabolites in vivo. Fluconazole was also found to be a potent inhibitor of the P4503A4-catalyzed formation of (R)-10-hydroxywarfarin (Ki = 15-18 microM) as well as the low KM P450 enzymes responsible for the formation of (R)-6-, (R)-7-, and (R)-8-hydroxywarfarin (Ki = 2-6 microM). By contrast, experiments with the P4501A2 inhibitor furafylline and cDNA-expressed P4501A2 indicate that fluconazole is a weak inhibitor of this enzyme (Ki > 800 microM), as measured by the inability of fluconazole to significantly suppress the P4501A2-dependent 6-hydroxylation of (R)-warfarin. The prediction generated from these studies, that fluconazole is a potent in vivo inhibitor of warfarin metabolism, , is tested in complementary studies reported in the accompanying article, "Warfarin-Fluconazole II".