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

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...

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Bibliographic Details
Published in:Clinical pharmacology and therapeutics 2013-11, Vol.94 (5), p.601-609
Main Authors: Shin, K-H, Choi, M H, Lim, K S, Yu, K-S, Jang, I-J, Cho, J-Y
Format: Article
Language:English
Subjects:
Adult
Biological and medical sciences
Biomarkers - blood
Biomarkers - urine
Cortisone - analogs & derivatives
Cortisone - urine
Cytochrome P-450 CYP3A - biosynthesis
Cytochrome P-450 CYP3A - metabolism
Cytochrome P-450 CYP3A Inhibitors
Enzyme Induction - drug effects
Gas Chromatography-Mass Spectrometry
Humans
Hydrocortisone - analogs & derivatives
Hydrocortisone - urine
Hydroxycholesterols - blood
Ketoconazole - pharmacology
Liver - enzymology
Male
Medical sciences
Metabolomics - methods
Midazolam - pharmacokinetics
Pharmacogenetics - methods
Pharmacology. Drug treatments
Rifampin - pharmacology
Young Adult
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Summary: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. Clinical Pharmacology & Therapeutics (2013); 94 5, 601–609. doi:10.1038/clpt.2013.128
ISSN:0009-9236
1532-6535
DOI:10.1038/clpt.2013.128