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Clin Pharmacol Ther. 2018 May;103(5):879-887. doi: 10.1002/cpt.856. Epub 2017 Oct 10.

Identification of ω- or (ω-1)-Hydroxylated Medium-Chain Acylcarnitines as Novel Urinary Biomarkers for CYP3A Activity.

Author information

1
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea.
2
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea.

Abstract

Quantitative models of endogenous metabolites are useful in predicting CYP3A-mediated drug-drug interactions. This study aimed to identify novel predictive markers for the magnitude of CYP3A induction and inhibition in male and female subjects using an untargeted metabolomics approach. Here we report five ω- or (ω-1)-hydroxylated medium-chain acylcarnitines as novel CYP3A4 markers. As CYP4 catalyzes the ω- or (ω-1)-hydroxylation of various medium-chain fatty acids (MCFAs), recombinant enzyme assays were used to determine the ω- and (ω-1)-hydroxylation activities of CYP3A4, CYP4A11, and CYP4F2. CYP3A4 catalyzed ω- and (ω-1)-hydroxylated MCFAs with the lowest Km and highest Vmax /Km values. Finally, we derived a model to predict midazolam clearance using these markers and demonstrated that the predictive model including three ω- or (ω-1)-hydroxylated medium-chain acylcarnitines, 6β-OH cortisol, and gender as covariates shows reliable predictability (r2 = 0.894).

PMID:
28877336
DOI:
10.1002/cpt.856

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