Polymorphic Expression of UGT1A9 is Associated with Variable Acetaminophen Glucuronidation in Neonates: A Population Pharmacokinetic and Pharmacogenetic Study

Linakis, Matthew W.; Cook, Sarah F.; Kumar, Shaun S.; Liu, Xiaoxi; Wilkins, Diana G.; Gaedigk, Roger; Gaedigk, Andrea; Sherwin, Catherine M.T.; Anker, John N. van den

doi:10.1007/s40262-018-0634-9

Cited by 17 publications

(14 citation statements)

References 38 publications

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“…22 Neonates with the UGT1A9 T 10 polymorphism, indicating insertion of an additional thymidine nucleotide, had a 42% reduction in clearance to APAP glucuronide as compared with their wild-type counterparts. 23 Other factors could also influence glucuronidation, and miR-375 was identified as a novel repressor of UGT1A-mediated hepatic APAP glucuronidation through reduced aryl hydrocarbon receptor (AhR) expression, which could predispose some individuals to increased risk for APAP-induced ALF. 24 Polymorphisms in sulfotransferases have also been shown to influence APAP metabolism.…”

Section: Acetaminophen Metabolismmentioning

confidence: 99%

Acetaminophen Hepatotoxicity

2019

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Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity. This insight led to the rapid introduction of N-acetylcysteine as a clinical antidote. However, more recently, substantial progress was made in further elucidating the detailed mechanisms of APAP-induced cell death. Mitochondrial protein adducts trigger a mitochondrial oxidant stress, which requires amplification through a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK) in the cytosol and translocation of phospho-JNK to the mitochondria. The enhanced oxidant stress is responsible for the membrane permeability transition pore opening and the membrane potential breakdown. The ensuing matrix swelling causes the release of intermembrane proteins such as endonuclease G, which translocate to the nucleus and induce DNA fragmentation. These pathophysiological signaling mechanisms can be additionally modulated by removing damaged mitochondria by autophagy and replacing them by mitochondrial biogenesis. Importantly, most of the mechanisms have been confirmed in human hepatocytes and indirectly through biomarkers in plasma of APAP overdose patients. The extensive necrosis caused by APAP overdose leads to a sterile inflammatory response. Although recruitment of inflammatory cells is necessary for removal of cell debris in preparation for regeneration, these cells have the potential to aggravate the injury. This review touches on the newest insight into the intracellular mechanisms of APAP-induced cells death and the resulting inflammatory response. Furthermore, it discusses the translation of these findings to humans and the emergence of new therapeutic interventions.

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Section: Acetaminophen Metabolismmentioning

confidence: 99%

Acetaminophen Hepatotoxicity

2019

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“…However, thinking of drug metabolism as being low in neonates and rising throughout infancy, early childhood, and prepuberty to reach adult levels in puberty is too simplistic. Genetics, comorbidity, and environmental issues further interact with these developmental changes: ontogeny is only 1 of the relevant covariates . Translation of the existing knowledge on ontogeny into age‐adjusted dosing guidelines and clinical trial design is a powerful tool to improve pharmacotherapy and clinical study design and to predict effects/side effects throughout childhood …”

Section: Drug Metabolismmentioning

confidence: 99%

“…Genetics, comorbidity, and environmental issues further interact with these developmental changes: ontogeny is only 1 of the relevant covariates. [90][91][92] Translation of the existing knowledge on ontogeny into age-adjusted dosing guidelines and clinical trial design is a powerful tool to improve pharmacotherapy and clinical study design and to predict effects/side effects throughout childhood. 89…”

Section: Maturational Changes Throughout Childhoodmentioning

confidence: 99%

Developmental Changes in Pharmacokinetics and Pharmacodynamics

Anker

Reed

Allegaert

et al. 2018

The Journal of Clinical Pharma

223

171

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Effective drug therapy to optimally influence disease requires an understanding of a drug's pharmacokinetic, pharmacodynamic, and pharmacogenomic interrelationships. In pediatrics, age is a continuum that can and does add variability in drug disposition and effect. This article addresses the many important factors that influence drug disposition and effect relative to age. What is known about the influence of maturation on the processes of drug absorption, distribution, metabolism, excretion, and drug receptor dynamics are outlined. Our state of understanding of many of these factors remains in flux, however, and only with additional study will we be able to better anticipate and model drug‐response relationships across the age continuum. Being able to continuously improve our care of the ill pediatric patient while simultaneously being able to accurately determine the utility of new drugs and chemical entities in this population requires our enhanced understanding of these disposition characteristics.

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“…Increased UGT1A9 expression due to carriage of UGT1A9 * 1b , which has a single-base insertion into the promotor region [−118(dT) 9>10 ], 29 has been associated with an increased risk of severe diarrhoea on irinotecan-based cancer treatment 30 and variability in neonatal clearance of acetaminophen (paracetamol). 31 The UGT1A9*1b allele is most common in Asian populations but is also found in Caucasians and African Americans. 29 , 32 …”

Section: Introductionmentioning

confidence: 99%

Evaluation of the effect of UGT1A1 polymorphisms on the pharmacokinetics of oral and long-acting injectable cabotegravir

Patel

Xue

King

et al. 2020

Journal of Antimicrobial Chemotherapy

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Background Cabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure. Objectives To investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokinetics (PK) and safety of oral cabotegravir (30 mg/day) and intramuscular cabotegravir LA (400 mg every 4 weeks or 600 mg every 8 weeks). Methods Plasma cabotegravir PK was assessed in 346 UGT-genotyped participants with and without UGT1A1 functional variants across six studies (four Phase I and two Phase II) of oral cabotegravir, including 215 HIV-infected participants who received oral cabotegravir followed by cabotegravir LA. Changes from baseline in total bilirubin and ALT were assessed in one study (LATTE; NCT01641809). Results Statistically significant (P < 0.05) associations were observed between UGT1A1 genotype and plasma cabotegravir PK parameters, with 28%–50% increases following oral cabotegravir [plasma cabotegravir concentration at the end of the dosing interval (Ctau), 1.50-fold; AUCtau, 1.41-fold; and Cmax, 1.28-fold] and 16%–24% increases following cabotegravir LA administration (48 week Ctau, 1.24-fold; AUCtau, 1.16-fold; and Cmax, 1.18-fold) among those with low-versus-normal genetically predicted UGT1A1 activity. A statistically significant (P < 10−5) association between predicted UGT1A1 activity and maximum change in total bilirubin was also observed (2.45-fold asymptomatic increase for low versus normal) without a corresponding change in ALT. Conclusions This modest increase in oral and parenteral cabotegravir exposure associated with a reduced function of UGT1A1 is not considered clinically relevant based on accumulated safety data; no dose adjustment is required.

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Polymorphic Expression of UGT1A9 is Associated with Variable Acetaminophen Glucuronidation in Neonates: A Population Pharmacokinetic and Pharmacogenetic Study

Abstract: This study shows a pharmacogenetic effect of an SV in the UGT1A9 promoter region on the metabolism of acetaminophen in neonates.

Cited by 17 publications

References 38 publications

Acetaminophen Hepatotoxicity

Acetaminophen Hepatotoxicity

Developmental Changes in Pharmacokinetics and Pharmacodynamics

Evaluation of the effect of UGT1A1 polymorphisms on the pharmacokinetics of oral and long-acting injectable cabotegravir

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