Evaluation of endogenous metabolic markers of hepatic CYP3A activity using metabolic profiling and midazolam clearance

K. H. Shin, M. H. Choi, K. S. Lim, Kyung-Sang Yu, In-Jin Jang, Joo-Youn Cho

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)601-609
Number of pages9
JournalClinical Pharmacology and Therapeutics
Volume94
Issue number5
DOIs
StatePublished - 8 Aug 2013

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Cytochrome P-450 CYP3A
Midazolam
Liver
Metabolomics
Ketoconazole
Rifampin
Healthy Volunteers
Genotype
Urine

Cite this

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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.",
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Evaluation of endogenous metabolic markers of hepatic CYP3A activity using metabolic profiling and midazolam clearance. / Shin, K. H.; Choi, M. H.; Lim, K. S.; Yu, Kyung-Sang; Jang, In-Jin; Cho, Joo-Youn.

In: Clinical Pharmacology and Therapeutics, Vol. 94, No. 5, 08.08.2013, p. 601-609.

Research output: Contribution to journalArticle

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