Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism
Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism
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DOI：
10.1016/s0009-9236(96)90177-0
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发表时间：
1996-05-01
影响因子：
6.7
通讯作者：
Wilkinson, GR
中科院分区：
文献类型：
--
作者：
Thummel, KE;OShea, D;Wilkinson, GR
目的：以咪达唑仑为模型化合物，确定人体肠道和肝脏代谢在 CYP3A 底物口服首过消除中的相对作用。方法：以随机方式向 20 名健康年轻受试者（10 名男性和 10 名女性）静脉注射（1 mg）或口服（2 mg）咪达唑仑，并确定药物及其 1'-羟基代谢物的处置。研究了 CYP3A 介导的人肝和肠微粒体形成 1'-羟基咪达唑仑的情况。 结果：咪达唑仑的全身清除率（370 +/- 114 ml/min [平均值 +/- SD]）或口服清除率（1413 +/- 807 ml/min）均未发现与性别相关的差异。尽管口服吸收完全，但测得的口服生物利用度平均比假设只有肝脏参与首过代谢的预测值低约 50%。肠道成分的药代动力学评估表明提取率（0.43 +/- 0.24）与肝脏的提取率（0.44 +/- 0.14）相似。 1'-羟基咪达唑仑在体外由肝和肠微粒体广泛但不同地形成，尽管肝脏制剂中的内在清除率 (V-max/K-m) 较高（540 +/- 747 对比 135 +/- 92 μl/min/mg 蛋白质），但这种差异并不具有统计学意义。结论：这些结果表明，小肠可能是系统前 CYP3A 介导的代谢的主要部位。此外，口服给药，这似乎代表了真正的首过效应。此外，肠道和肝脏代谢可能是口服咪达唑仑和类似 CYP3A 底物后个体差异的重要因素。最后，CYP3A 的肠道定位可能在基于代谢的药物相互作用中具有重要意义。
Objective: To determine in humans the relative roles of intestinal and hepatic metabolism in the oral first-pass elimination of a CYP3A substrate using midazolam as a model compound.Methods: Midazolam was administered intravenously (1 mg) or orally (2 mg) to 20 healthy young subjects (10 men and 10 women) in a random fashion, and the disposition of the drug and its 1'-hydroxy metabolite were determined, In separate in vitro studies, the CYP3A-mediated formation of 1'-hydroxymidazolam by human hepatic and intestinal microsomes was investigated.Results: No gender-related differences were noted in either the systemic (370 +/- 114 ml/min [mean +/- SD]) or oral (1413 +/- 807 ml/min) clearance values of midazolam. Despite complete oral absorption, measured oral bioavailability was on average about 50% less than that predicted on the assumption that only the liver contributed to first-pass metabolism. Pharmacokinetic estimation of the intestinal component indicated an extraction ratio (0.43 +/- 0.24) that was similar to that of the liver (0.44 +/- 0.14). 1'-Hydroxymidazolam was extensively but variably formed in vitro by both hepatic and intestinal microsomes and, although the intrinsic clearance (V-max/K-m) was higher in the liver preparations (540 +/- 747 versus 135 +/- 92 mu l/min/mg protein), this difference was not statistically significant.Conclusions: These results show that the small intestine can be a major site for presystemic, CYP3A-mediated metabolism after oral administration, Moreover, it appears that this represents a true first-pass effect. In addition, intestinal and hepatic metabolism may be important factors in interindividual variability in disposition after oral administration of midazolam and similar CYP3A substrates. Finally, intestinal localization of CYP3A may be significant in metabolism-based drug-drug interactions.