Matthew W Linakis1,2, Sarah F Cook3, Shaun S Kumar1, Xiaoxi Liu1, Diana G Wilkins4,5, Roger Gaedigk6, Andrea Gaedigk6, Catherine M T Sherwin7,8, John N van den Anker9,10. 1. Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, 295 Chipeta Way, Suite 1S100, Salt Lake City, UT, 84108, USA. 2. Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 30 S 2000 E, Salt Lake City, UT, USA. 3. Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA. 4. Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, Salt Lake City, UT, USA. 5. Division of Medical Laboratory Sciences, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA. 6. Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Kansas City and School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA. 7. Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, 295 Chipeta Way, Suite 1S100, Salt Lake City, UT, 84108, USA. Catherine.Sherwin@hsc.utah.edu. 8. Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 30 S 2000 E, Salt Lake City, UT, USA. Catherine.Sherwin@hsc.utah.edu. 9. Division of Clinical Pharmacology, Children's National Health System, Washington, DC, USA. 10. Division of Paediatric Pharmacology and Pharmacometrics, University of Basel Children's Hospital, Basel, Switzerland.
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.
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 UGT1A9T10 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.
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