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

Journal article
Authors Deepak Kumar Bhatt
Aanchal Mehrotra
Andrea Gaedigk
Revathi Chapa
Abdul Basit
Haeyoung Zhang
Prachi Choudhari
Mikael Boberg
Robin E. Pearce
Roger Gaedigk
Ulrich Broeckel
J. Steven Leeder
Bhagwat Prasad
Published in Clinical Pharmacology and Therapeutics
Volume 105
Issue 1
Pages 131-141
ISSN 00099236
Publication year 2018
Published at Institute of Neuroscience and Physiology, Department of Pharmacology
Pages 131-141
Language en
Links https://ascpt.onlinelibrary.wiley.c...
Subject categories Pharmaceutical pharmacology

Abstract

© 2018 The American Society for Clinical Pharmacology and Therapeutics. 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.

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