Ontogeny of Hepatic and Renal Systemic Clearance Pathways in Infants: Part I

Authors: Alcorn J.; McNamara P.J.

Source: Clinical Pharmacokinetics, Volume 41, Number 12, 2002 , pp. 959-998(40)

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Abstract:

Dramatic developmental changes in the physiological and biochemical processes that govern drug pharmacokinetics and pharmacodynamics occur during the first year of life. These changes may have significant consequences for the way infants respond to and deal with drugs. The ontogenesis of systemic clearance mechanisms is probably the most critical determinant of a pharmacological response in the developing infant. In recent years, advances in molecular techniques and an increased availability of fetal and infant tissues have afforded enhanced insight into the ontogeny of clearance mechanisms. Information from these studies is reviewed to highlight the dynamic and complex nature of developmental changes in clearance mechanisms in infants during the first year of life.

Hepatic and renal elimination mechanisms constitute the two principal clearance pathways of the developing infant. Drug metabolising enzyme activity is primarily responsible for the hepatic clearance of many drugs. In general, when compared with adult activity levels normalised to amount of hepatic microsomal protein, hepatic cytochrome P450-mediated metabolism and the phase II reactions of glucuronidation, glutathione conjugation and acetylation are deficient in the neonate, but sulfate conjugation is an efficient pathway at birth. Parturition triggers the dramatic development of drug metabolising enzymes, and each enzyme demonstrates an independent rate and pattern of maturation. Marked interindividual variability is associated with their developmental expression, making the ontogenesis of hepatic metabolism a highly variable process. By the first year of life, most enzymes have matured to adult activity levels.

When compared with adult values, renal clearance mechanisms are compromised at birth. Dramatic increases in renal function occur in the ensuing postpartum period, and by 6 months of age glomerular filtration rate normalised to bodyweight has approached adult values. Maturation of renal tubular functions exhibits a more protracted time course of development, resulting in a glomerulotubular imbalance. This imbalance exists until adult renal tubule function values are approached by 1 year of age. The ontogeny of hepatic biliary and renal tubular transport processes and their impact on the elimination of drugs remain largely unknown.

The summary of the current understanding of the ontogeny of individual pathways of hepatic and renal elimination presented in this review should serve as a basis for the continued accruement of age-specific information concerning the ontogeny of clearance mechanisms in infants. Such information can only help to improve the pharmacotherapeutic management of paediatric patients.

The dearth of pharmacological data specific for the infant population poses a significant obstacle to the successful pharmacotherapeutic management of such patients. Until recently, moral, ethical and legal issues had seriously impeded rigorous scientific investigation into paediatric drug pharmacokinetics, such that most marketed drugs merely contain disclaimers for their use in these populations. In the absence of age-specific pharmacological data, infant dosage regimens become based upon information available only in adult patient populations. Despite their prudence and conservatism, empirical approaches to pharmacotherapy still produce suboptimal, serious and even lethal consequences of drug exposure in infants. Such adverse outcomes exist because physiological and biochemical maturation of pharmacokinetic and pharmacodynamic characteristics alter the pharmacology and potential toxicity of drugs in infants as compared with adult patients.Systemic clearance constitutes a critical pharmacokinetic parameter in the determination of a pharmacological response. Yet the exact impact of clearance pathway ontogenesis on an infants capacity to eliminate drugs remains largely unknown. With recent improvements in molecular technology, more precise information on the development of individual clearance pathways has become available. Part I of this review provides a comprehensive and descriptive account of the ontogenesis of hepatic and renal elimination mechanisms, principally based upon recently available molecular and in vitro enzyme activity data for hepatic metabolic clearance mechanisms and in vivo probe substrate data for renal clearance due to glomerular filtration. Such descriptions highlight the dynamic nature of these developmental processes during early postnatal life and how these processes may affect drug elimination and pharmacological response in infants. In general, hepatic and renal clearance mechanisms are underdeveloped and inefficient in the neonate, a condition further exacerbated in the premature infant. These mechanisms undergo dramatic developmental changes following birth and demonstrate different rates and patterns of maturation to adult values. Discussion herein of the ontogeny of such hepatic

Keywords: Clinical pharmacokinetics; Infants; Liver function; Low birth weight; Metabolism; Neonates; Renal function

Language: English

Document Type: Review article

Affiliations: 1: Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA *

Publication date: 2002-01-01

Ontogeny of Hepatic and Renal Systemic Clearance Pathways in Infants: Part I

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