1. Polymorphic Expression of UGT1A9 is Associated with Variable Acetaminophen Glucuronidation in Neonates: A Population Pharmacokinetic and Pharmacogenetic Study.
- Author
-
Linakis, Matthew W., Cook, Sarah F., Kumar, Shaun S., Liu, Xiaoxi, Wilkins, Diana G., Gaedigk, Roger, Gaedigk, Andrea, Sherwin, Catherine M. T., and van den Anker, John N.
- Subjects
NEWBORN infants ,ACETAMINOPHEN ,GLUCURONIDATION ,PHARMACOKINETICS ,PHARMACOGENOMICS ,BIOLOGICAL models ,COMPARATIVE studies ,GENES ,GENETIC polymorphisms ,LONGITUDINAL method ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,TRANSFERASES ,EVALUATION research ,ACYCLIC acids - Abstract
Introduction: 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.Methods: 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.Results: 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.Conclusion: This study shows a pharmacogenetic effect of an SV in the UGT1A9 promoter region on the metabolism of acetaminophen in neonates. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF