Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Clin Pharmacol Ther. 2013 Nov;94(5):601-9. doi: 10.1038/clpt.2013.128. Epub 2013 Jun 19.
This study aimed to evaluate endogenous metabolic markers of hepatic cytochrome P450 (CYP)3A activity in healthy subjects using a metabolomics approach. Twenty-four subjects received the following medication during the following three study periods: 1 mg of i.v. midazolam alone (control phase), 1 mg of i.v. midazolam after 4 days of pretreatment with 400 mg of ketoconazole once daily (CYP3A-inhibited phase), and 2.5 mg of i.v. midazolam after 10 days of pretreatment with 600 mg of rifampicin once daily (CYP3A-induced phase). During each study period, 24 h before and after the administration of midazolam, urine samples were collected at 12-h intervals for metabolomic analyses. We derived an equation to predict midazolam clearance (CL) based on several of these markers. We demonstrated that a combination of the concentrations and ratios of several endogenous metabolites and the CYP3A5*3 genotype is a reliable predictive marker of hepatic CYP3A activity as assessed by i.v. administration of midazolam.
本研究旨在采用代谢组学方法评估健康受试者肝细胞色素 P450（CYP）3A 活性的内源性代谢标志物。24 名受试者在以下三个研究期间接受以下药物治疗：单独静脉注射 1 毫克咪达唑仑（对照期）、每天口服 400 毫克酮康唑预处理 4 天后静脉注射 1 毫克咪达唑仑（CYP3A 抑制期）和每天口服 600 毫克利福平预处理 10 天后静脉注射 2.5 毫克咪达唑仑（CYP3A 诱导期）。在每个研究期间，咪达唑仑给药前 24 小时和给药后，每隔 12 小时采集尿液样本进行代谢组学分析。我们得出了一个基于这些标志物中的几个来预测咪达唑仑清除率（CL）的方程。我们证明，几种内源性代谢物的浓度和比值以及 CYP3A5*3 基因型的组合是通过静脉注射咪达唑仑评估肝 CYP3A 活性的可靠预测标志物。
