Determinants of Drug Metabolism in Early Neonatal Life

Karel      Allegaert; John   N.   van den Anker; Gunnar      Naulaers; Jan      de Hoon

Abstract

Clinical pharmacology intends to predict drug-specific effects and side effects based on pharmacokinetics (i.e. absorption, distribution, metabolism and elimination) and pharmacodynamics (i.e. dose/effect relationship). Developmental pharmacology focuses on the maturational aspects of these phenomena during perinatal life and later stages of infancy. In general, phenotypic variation in drug metabolism is based on constitutional, environmental and genetic factors but in early neonatal life, it mainly reflects ontogeny. Although the major site of drug metabolism is the liver, the gastrointestinal tract, blood cells and other organs like kidneys or lungs might also be involved in drug metabolism. Important alterations in hepatic drug metabolism occur in early neonatal life. These alterations are of relevance when agedependent aspects of pharmacokinetics, -dynamics or toxicology are considered. Age dependent maturation of various phase I and II processes will be illustrated based on recently reported observations on the in vivo disposition of various analgesics (paracetamol, tramadol) in human neonates and young infants. However, age only in part explains the interindividual variability observed. Therefore, concerted efforts should be developed to simultaneously assess the impact of age, environmental factors, comorbidity and polymorphisms in this specific population. The implementation of multivariable models like non-linear mixed effects (NONMEM) models hereby provide us with the tools to disentangle the impact of various co-variables in this specific population.

Keywords: Metabolism, ontogeny, cytochrome P450 iso-enzymes, uridine diphosphate glucuronosyltransferase iso-enzymes, tramadol, paracetamol

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