Hepatic drug metabolism in pediatrics : investigating the neonatal and juvenile (mini)pig as a translational model
Despite considerable progress in understanding drug metabolism in the human pediatric population, data remains scarce in (preterm) neonates and infants. Improving our knowledge of the ADME properties (i.e., absorption, distribution, metabolism, and excretion) in this vulnerable age group is of utmost importance to avoid suboptimal dosing, which may lead to adverse drug reactions. The adult (mini)pig is a representative model for hepatic drug metabolism in humans, but data in the (preterm) neonatal and juvenile population remain scarce. Therefore, the goal of this thesis was thus to further characterize hepatic phase I (cytochrome P450 (CYP) enzymes) and phase II (uridine 5’-diphospho-glucuronosyltransferase (UGT) enzymes) enzyme ontogeny in neonatal and juvenile (mini)pigs. First, hepatic phase I drug metabolism on protein level was characterized in fetal, neonatal, juvenile and adult Göttingen Minipigs. Hepatic CYP protein abundance was investigated in liver microsomes using an LC-MS/MS approach. Various ontogeny profiles were discovered which were in line with observations in man. Sex-related differences were detected with highest expression in female compared to male minipigs. CYP protein abundance was correlated with earlier observed CYP enzyme activity. Next, the translational potential of the preterm pig model for human neonatal drug metabolism was investigated. The aim of this study was to examine the ontogeny of CYP3A and UGT enzyme activity in the liver of preterm and term-born domestic piglets. In addition, the effect of postconceptional and postnatal age on the onset of enzyme activity was examined. UGT activity showed a significant postnatal increase in preterm and term-born piglets from birth onwards. CYP3A enzyme activity was only detected in preterm-born piglets at weaning while a gradual increase was observed in term-born piglets from postnatal day 11 onwards. In both groups, enzyme activity was lower in the preterm compared to the term group, suggesting that postconceptional age rather than postnatal age is affecting CYP3A and UGT enzyme ontogeny in the pig. Finally, the data obtained in this thesis contribute to a better understanding of the biotransformation capacity in the (mini)pig. In general, large similarities with human pediatric hepatic drug metabolism were found which encourages the use of the pig as nonclinical species for pediatric drug development.
Antwerp : University of Antwerp, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Department of Veterinary Sciences , 2023
134 p.
Supervisor: Van Cruchten, Steven [Supervisor]
Supervisor: van Ginneken, Chris [Supervisor]
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Creation 28.09.2023
Last edited 13.10.2023
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