title: Evaluation of endogenous metabolic markers of hepatic CYP3A activity using metabolic profiling and midazolam clearance.
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.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: K-H
authors.initials: KH
authors.lastname: Shin
authors.forename: M H
authors.initials: MH
authors.lastname: Choi
authors.forename: K S
authors.initials: KS
authors.lastname: Lim
authors.forename: K-S
authors.initials: KS
authors.lastname: Yu
authors.forename: I-J
authors.initials: IJ
authors.lastname: Jang
authors.forename: J-Y
authors.initials: JY
authors.lastname: Cho
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003348:Cortisone / Q000031:analogs & derivatives / Q000652:urine; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004790:Enzyme Induction / Q000187:drug effects; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000652:urine; D006888:Hydroxycholesterols / Q000097:blood; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D055432:Metabolomics / Q000379:methods; D008874:Midazolam / Q000493:pharmacokinetics*; D010597:Pharmacogenetics / Q000379:methods; D012293:Rifampin / Q000494:pharmacology; D055815:Young Adult
chemical_list: C485511:6 beta-hydroxycortisone; D015415:Biomarkers; D065692:Cytochrome P-450 CYP3A Inhibitors; D006888:Hydroxycholesterols; C099828:cholest-5-ene-3,4-diol; C001380:6 beta-hydroxycortisol; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D007654:Ketoconazole; D003348:Cortisone; D012293:Rifampin; D006854:Hydrocortisone