Evaluation of Endogenous Metabolic Markers of Hepatic CYP3A Activity Using Metabolic Profiling and Midazolam Clearance
- Evaluation of Endogenous Metabolic Markers of Hepatic CYP3A Activity Using Metabolic Profiling and Midazolam Clearance
- 신광희; 최만호; 임경상; 유경수; 장인진; 조주연
- metabolomics; steroid; midazolam; rifampicin; drug evaluation; cytochrome P450
- Issue Date
- Clinical pharmacology and therapeutics
- VOL 94, NO 5, 601-609
- 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.
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