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Polymorphic Expression of UGT1A9 is Associated with Variable Acetaminophen Glucuronidation in Neonates: A Population Pharmacokinetic and Pharmacogenetic Study.
- Source :
-
Clinical Pharmacokinetics . Oct2018, Vol. 57 Issue 10, p1325-1336. 12p. - Publication Year :
- 2018
-
Abstract
- <bold>Introduction: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>This study shows a pharmacogenetic effect of an SV in the UGT1A9 promoter region on the metabolism of acetaminophen in neonates. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03125963
- Volume :
- 57
- Issue :
- 10
- Database :
- Academic Search Index
- Journal :
- Clinical Pharmacokinetics
- Publication Type :
- Academic Journal
- Accession number :
- 131688361
- Full Text :
- https://doi.org/10.1007/s40262-018-0634-9