咪唑安定
首过效应
药代动力学
生物利用度
药理学
药物代谢
新陈代谢
口服
化学
药物相互作用
门静脉
第一次通过
药品
医学
内科学
镇静
算术
数学
作者
Run Liu,Qingqing Wang,Zihou Liu,Like Xie,Zhipeng Diao,Ying Peng,Guangji Wang,Jianguo Sun
出处
期刊:Xenobiotica
[Informa]
日期:2023-03-04
卷期号:53 (3): 184-192
标识
DOI:10.1080/00498254.2023.2200524
摘要
To characterise the dose-dependent pharmacokinetics of midazolam and evaluate the intestinal and hepatic first-pass effects on midazolam in Sprague-Dawley rats, the concentrations and area under the concentration-time curve (AUC) of midazolam in the portal and systemic plasma were simultaneously determined with a double cannulation method.It was found that about 75% of the dose was left in the portal blood with different oral administration doses, while the bioavailability in the liver was 37.86% at 20 mg/kg, significantly higher than 9.16% at 2 mg/kg.The disproportional increase in AUC of midazolam and significant decrease in exposure of metabolites were observed in systemic plasma after hepatic portal vein administration. And in the in vitro study, the formation rate of the metabolites of midazolam significantly decreased when midazolam was at 300 μM compared with 100 μM.These results indicated that not only the saturation of first-pass metabolism but also the inhibition of hepatic metabolism is responsible for the nonlinear PK of midazolam. Thus, a rational dose should be chosen when midazolam is used as a probe in the drug-drug interaction study, particularly for orally administered drugs that undergo hepatic first-pass metabolism.
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