Age-Dependent Abundance of CYP450 Enzymes Involved in Metronidazole Metabolism: Application to Pediatric PBPK Modeling.

Publisher: Wiley Country of Publication: United States NLM ID: 0372741 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-6535 (Electronic) Linking ISSN: 00099236 NLM ISO Abbreviation: Clin Pharmacol Ther Subsets: MEDLINE

Publication: 2015- : Hoboken, NJ : Wiley
Original Publication: St. Louis : C.V. Mosby

Metronidazole*/pharmacokinetics ; Metronidazole*/metabolism ; Microsomes, Liver*/metabolism ; Models, Biological* ; Cytochrome P-450 Enzyme System*/metabolism ; Cytochrome P-450 Enzyme System*/genetics; Humans ; Child ; Female ; Male ; Child, Preschool ; Infant ; Age Factors ; Adult ; Infant, Newborn ; Adolescent ; Young Adult ; Middle Aged ; Genotype ; Proteomics/methods

The expression of cytochrome P450 (CYP) enzymes is highly variable and associated with factors, such as age, genotype, sex, and disease states. In this study, quantification of metronidazole metabolizing CYP isoforms (CYP2A6, CYP2E1, CYP3A4, CYP3A5, and CYP3A7) in human liver microsomes from 115 children and 35 adults was performed using a quantitative proteomics method. The data confirmed age-dependent increase in CYP2A6, CYP2E1, and CYP3A4 abundance, whereas, as expected, CYP3A7 abundance showed postnatal decrease with age. In particular, the fold difference (neonatal to adulthood levels) in the protein abundance of CYP2A6, CYP2E1, and CYP3A4 was 14, 11, and 20, respectively. In contrast, protein abundance of CYP3A7 was > 125-fold higher in the liver microsomes of neonates than of adults. The abundance of CYP2A6 and CYP3A5 was associated with genotypes, rs4803381 and rs776746, respectively. A proteomics-informed physiologically based pharmacokinetic (PBPK) model was developed to describe the pharmacokinetics of metronidazole and its primary metabolite, 2-hydroxymethylmetronidazole. The model revealed an increase in the metabolite-to-parent ratio with age and showed a strong correlation between CYP2A6 abundance and metabolite formation (r ²  = 0.75). Notably, the estimated contribution of CYP3A7 was ~ 75% in metronidazole clearance in neonates. These data suggest that variability in CYP2A6 and CYP3A7 in younger children poses the risk of variable pharmacokinetics of metronidazole and its active metabolite with a potential impact on drug efficacy and safety. No sex-dependent difference was observed in the protein abundance of the studied CYPs. The successful integration of hepatic CYP ontogeny data derived from a large liver bank into the pediatric PBPK model of metronidazole can be extended to other drugs metabolized by the studied CYPs.
(© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

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Eunice Kennedy Shriver National Institute of Child Health and Human Development; R01.HD081299 United States GF NIH HHS

140QMO216E (Metronidazole)
9035-51-2 (Cytochrome P-450 Enzyme System)

Date Created: 20240702 Date Completed: 20241004 Latest Revision: 20241004

20241008

10.1002/cpt.3354

38955794