芬太尼抑制咪达唑仑的代谢：体外对细胞色素P450 3A4的竞争性抑制。

Fentanyl inhibits metabolism of midazolam: competitive inhibition of CYP3A4 in vitro.

作者信息

Oda Y, Mizutani K, Hase I, Nakamoto T, Hamaoka N, Asada A

机构信息

Department of Anesthesiology and Intensive Care Medicine, Osaka City University Medical School, Japan.

出版信息

Br J Anaesth. 1999 Jun;82(6):900-3. doi: 10.1093/bja/82.6.900.

DOI:10.1093/bja/82.6.900

PMID:10562786

Abstract

Fentanyl decreases clearance of midazolam administered i.v., but the mechanism remains unclear. To elucidate this mechanism, we have investigated the effect of fentanyl on metabolism of midazolam using human hepatic microsomes and recombinant cytochrome P450 isoforms (n = 6). Midazolam was metabolized to l'-hydroxymidazolam (l'-OH MDZ) by human hepatic microsomes, with a Michaelis-Menten constant (K(m)) of 5.0 (SD 2.7) mumol litre-1. Fentanyl competitively inhibited metabolism of midazolam in human hepatic microsomes, with an inhibition constant (Ki) of 26.8 (12.4) mumol litre-1. Of the seven representative human hepatic P450 isoforms, CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4, only CYP3A4 catalysed hydroxylation of midazolam, with a K(m) of 3.6 (0.8) mumol liter-1. Fentanyl competitively inhibited metabolism of midazolam to l'-OH MDZ by CYP3A4, with a Ki of 24.2 (6.8) mumol litre-1, comparable with the Ki obtained in human hepatic microsomes. These findings indicate that fentanyl competitively inhibits metabolism of midazolam by CYP3A4.

摘要

芬太尼可降低静脉注射咪达唑仑的清除率，但其机制尚不清楚。为阐明该机制，我们利用人肝微粒体和重组细胞色素P450同工酶（n = 6）研究了芬太尼对咪达唑仑代谢的影响。人肝微粒体将咪达唑仑代谢为1'-羟基咪达唑仑（1'-OH MDZ），米氏常数（K(m)）为5.0（标准差2.7）μmol·L-1。芬太尼竞争性抑制人肝微粒体中咪达唑仑的代谢，抑制常数（Ki）为26.8（12.4）μmol·L-1。在七种代表性的人肝P450同工酶CYP1A2、2A6、2C9、2C19、2D6、2E1和3A4中，只有CYP3A4催化咪达唑仑的羟基化反应，K(m)为3.6（0.8）μmol·L-1。芬太尼竞争性抑制CYP3A4将咪达唑仑代谢为1'-OH MDZ，Ki为24.2（6.8）μmol·L-1，与人肝微粒体中获得的Ki相当。这些发现表明，芬太尼竞争性抑制CYP3A4介导的咪达唑仑代谢。