Polymorphic Expression of UGT1A9 is Associated with Variable Acetaminophen Glucuronidation in Neonates: A Population Pharmacokinetic and Pharmacogenetic Study
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Acetaminophen (paracetamol, APAP) is widely used as an analgesic and antipyretic drug in children and neonates. A number of enzymes contribute to the metabolism of acetaminophen, and genetic factors might be important to explain variability in acetaminophen metabolism among individuals.
The current investigation utilized a previously published parent–metabolite population pharmacokinetic model describing acetaminophen glucuronidation, sulfation, and oxidation to examine the potential role of genetic variability on the relevant metabolic pathways. Neonates were administered 30-min intravenous infusions of acetaminophen 15 mg/kg every 12 h (< 28 weeks’ gestational age [GA]) or every 8 h (≥ 28 weeks GA) for 48 h. A total of 18 sequence variations (SVs) in UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and cytochrome P450 (CYP) genes from 33 neonates (aged 1–26 days) were examined in a stepwise manner for an effect on the metabolic formation clearance of acetaminophen by glucuronidation (UGT), sulfation (SULT), and oxidation (CYP). The stepwise covariate modeling procedure was performed using NONMEM® version 7.3.
Incorporation of genotype as a covariate for one SV located in the UGT1A9 gene promoter region (rs3832043, − 118 > insT, T9 > T10) significantly improved model fit (likelihood ratio test, p < 0.001) and reduced between-subject variability in glucuronide formation clearance. Individuals with the UGT1A9 T10 polymorphism, indicating insertion of an additional thymidine nucleotide, had a 42% reduction in clearance to APAP-glucuronide as compared to their wild-type counterparts.
This study shows a pharmacogenetic effect of an SV in the UGT1A9 promoter region on the metabolism of acetaminophen in neonates.
The authors would like to acknowledge Drs. Chris Stockmann, Samira Samiee-Zafarghandy, Amber King, Nina Deutsch, and Elaine Williams for their contribution to the original model-building process. They would additionally like to thank Dr. Joseph Rower for his insightful suggestions and Mrs. Erika Abbott for technical support for genotype analyses.
Compliance with Ethical Standards
Conflict of interest
Matthew W. Linakis, Sarah F. Cook, Shaun S. Kumar, Xiaoxi Liu, Diana G. Wilkins, Roger Gaedigk, Andrea Gaedigk, Catherine M.T. Sherwin, and John N. van den Anker all declare that they have no conflicts of interest that might be relevant to the contents of this article.
This work was supported by National Institutes of Health grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD060543, to John N. van den Anker) and the National Center for Advancing Translational Sciences (UL1TR000075, to the Children’s National Health System), and by a contract for analytical laboratory services from McNeil Consumer Healthcare (Division of McNEIL-PPC, Inc., Fort Washington, PA, USA, to Diana G. Wilkins). ML was supported by a Pre-Doctoral Fellowship in Clinical Pharmaceutics from the American Foundation for Pharmaceutical Education.
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