Evaluation of Endogenous Metabolic Markers of Hepatic CYP3A Activity Using Metabolic Profiling and Midazolam Clearance

Title
Evaluation of Endogenous Metabolic Markers of Hepatic CYP3A Activity Using Metabolic Profiling and Midazolam Clearance
Authors
신광희최만호임경상유경수장인진조주연
Keywords
metabolomics; steroid; midazolam; rifampicin; drug evaluation; cytochrome P450
Issue Date
2013-11
Publisher
Clinical pharmacology and therapeutics
Citation
VOL 94, NO 5, 601-609
Abstract
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.
URI
http://pubs.kist.re.kr/handle/201004/46104
ISSN
00099236
Appears in Collections:
KIST Publication > Article
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