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Clin Pharmacol Ther. 2019 Jan;105(1):131-141. doi: 10.1002/cpt.1109. Epub 2018 Jul 12.

Age- and Genotype-Dependent Variability in the Protein Abundance and Activity of Six Major Uridine Diphosphate-Glucuronosyltransferases in Human Liver.

Author information

1
Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
2
Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy-Kansas City, Missouri, and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
3
Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
4
Section of Genomic Pediatrics, Department of Pediatrics, and Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Abstract

The ontogeny of hepatic uridine diphosphate-glucuronosyltransferases (UGTs) was investigated by determining their protein abundance in human liver microsomes isolated from 136 pediatric (0-18 years) and 35 adult (age >18 years) donors using liquid chromatography / tandem mass spectrometry (LC-MS/MS) proteomics. Microsomal protein abundances of UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 increased by ∼8, 55, 35, 33, 8, and 3-fold from neonates to adults, respectively. The estimated age at which 50% of the adult protein abundance is observed for these UGT isoforms was between 2.6-10.3 years. Measured in vitro activity was generally consistent with the protein data. UGT1A1 protein abundance was associated with multiple single nucleotide polymorphisms exhibiting noticeable ontogeny-genotype interplay. UGT2B15 rs1902023 (*2) was associated with decreased protein activity without any change in protein abundance. Taken together, these data are invaluable to facilitate the prediction of drug disposition in children using physiologically based pharmacokinetic modeling as demonstrated here for zidovudine and morphine.

PMID:
29737521
PMCID:
PMC6222000
[Available on 2020-01-01]
DOI:
10.1002/cpt.1109

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