Midazolam hydroxylation by human liver microsomes in vitro: Inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents
Midazolam hydroxylation by human liver microsomes in vitro: Inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents
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DOI：
10.1002/j.1552-4604.1996.tb04251.x
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发表时间：
1996-09-01
影响因子：
2.9
通讯作者：
Shader, RI
中科院分区：
文献类型：
--
作者：
vonMoltke, LL;Greenblatt, DJ;Shader, RI
本文研究了咪唑苯并二氮杂安定体外生物转化为羟基和4-羟基代谢物。铜-羟基咪达唑仑的形成是一个高亲和力(K-m=3.3mU·mol/L)的米氏-曼腾过程，在高浓度咪达唑仑时底物抑制。4-羟基咪唑仑的形成具有较低的表观亲和力(57mU/L)，底物抑制作用很小。基于两个途径的V-max/K-m比值的比较，估计α-羟基咪达唑仑的形成占净本征清除量的95%。3种唑类抗真菌药物对咪达唑仑的体外代谢均有抑制作用，抑制作用与竞争机制基本一致。对α-羟基咪达唑仑形成的平均竞争抑制常数(K-I)分别为酮康唑0.0037、伊曲康唑和氟康唑，分别为0.0037、0.27mU/L和1.27mU/L。体外-体内模型预测了酮康唑或伊曲康唑合用对咪达唑仑口服清除的抑制作用，预测的抑制作用与临床药代动力学研究中观察到的相互作用一致。选择性5-羟色胺再摄取抑制剂(SSRI)抗抑郁药氟西汀及其主要代谢物诺氟西汀也是咪达唑仑生物转化的两条途径的抑制剂，其中诺氟西汀是比氟西汀更有效的抑制剂。这一发现与其他体外研究和临床研究的结果一致，表明氟西汀可能主要通过其代谢物诺氟西汀损害P450-3A底物的清除。
Biotransformation of the imidazobenzodiazepine midazolam to its oc-hydroxy and 4-hydroxy metabolites was studied in vitro using human liver microsomal preparations, Formation of cu-hydroxy-midazolam was a high-affinity (K-m = 3.3 mu mol/L) Michaelis-Menten process coupled with substrate inhibition at high concentrations of midazolam. Formation of 4-hydroxymidazolam had much lower apparent affinity (57 mu mol/L), with minimal evidence of substrate inhibition. Based on comparison of V-max/K-m ratios for the two pathways, alpha-hydroxy-midazolam formation was estimated to account for 95% of net intrinsic clearance. Three azole antifungal agents were inhibitors of midazolam metabolism in vitro, with inhibition being largely consistent with a competitive mechanism. Mean competitive inhibition constants (K-i) versus alpha-hydroxy-midazolam formation were 0.0037 mu mol/L for ketoconazole, 0.27 mu mol/L for itraconazole, and 1.27 mu mol/L for fluconazole, An in vitro-in vivo scaling model predicted inhibition of oral midazolam clearance due to coadministration of ketoconazole or itraconazole; the predicted inhibition was consistent with observed interactions in clinical pharmacokinetic studies. The selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine and its principal metabolite, norfluoxetine, also were inhibitors of both pathways of midazolam biotransformation, with norfluoxetine being a much more potent inhibitor than was fluoxetine itself. This finding is consistent with results of other in vitro studies and of clinical studies, indicating that fluoxetine, largely via its metabolite norfluoxetine, may impair clearance of P450-3A substrates.