Developmental Pharmacology: A Review of its Application to Clinical and Basic Science

Abstract

Drugs administered to the maturing host may (a) be used to alleviate diseases peculiar to his age group, (b) undergo alterations in metabolic fate and distribution to influence therapeutic effectiveness as compared with adults, or (c) show unexpected adverse effects as a result of systems placed at risk during development. Pharmacologic treatment of neonatal "physio logic " hyperbilirubinemia has been studied, and drugs undoubtedly will be designed for a specific effect on other diseases characterized by a slow rate of enzyme (or transport mechanism) maturation. Many developmental phar macology studies have considered the effect of host physiology on actions of a drug or, conversely, the effect of a drug on the host. For example, failure in drug efficacy may be secondary to a low conversion of the parent drug to active metabolite (host effect on drug) or structural malformations may be the result of drug action on a developing tissue (drug effect on host). Dif ferences in clinical response or potential toxicity for a drug are demon strated by comparative studies in the adult versus the young. Of more im portance, however, is an explanation for the observed age-related differ ences in drug action. Such explanations are often broadly applicable to in vestigations with adults and enhance rational therapeutics in children. Un fortunately, more age-related drug actions have been described than ex plained. Developmental pharmacologists must now accept the challenge to build programs that encourage observation and explanation of drug-host in teractions on an age continuum (1).This review will cite studies to illustrate the three areas of developmen tal pharmacology outlined above. The effect of enzyme inducing agents on hyperbilirubinemia will be considered as an example of drug use for an ill ness commonly found in children. The development of liver mixed function oxidase activity as influenced by hormones will illustrate modification of drug fate by age of the host. Brief reference to tetracycline effects on teeth 1 This monograph was prepared with support from the Clinical Pharmacology

Hormonal Regulation of Hepatic Drug-Metabolizing Enzyme Activity During Adolescence

“…(43) Estrogens, in contrast, have been shown to decrease hepatic microsomal activity and drug clearance in rodents via a reduction in the amount of microsomal DME protein. (44, 45) The reported effects of progesterones on DME activity are variable and inconsistent with some investigations reporting an inhibitory effect (46) and others reporting an inductive effect. (44)…”

Developmental Aspects of the Hepatic Cytochrome P450 Monooxygenase System

“…Many of the infants were exposed to phenobarbital along with DPH, and the barbiturate (or DPH) could accelerate maturation of oxidative (170,171) as well as conjugative (e.g. 15,16) processes. No dependence of DPH elimination rate on coincident exposure to phe nobarbital was apparent.…”

Developmental aspects of hepatic glutathione S-transferase activities in male rats

“…Pharmacology, Sylvius labs of the University, P.O. Box 9503, 2300 RA LEIDEN, The Netherlands certain drugs and other xenobiotics that are relatively safe when administered to adults (7,8). It has been shown that the deficiency of many drug-metabolizing enzymes in foetuses and neonates is, at least partly, responsible for the increased toxicity in these organisms of compounds which have to be detoxified metabolically.…”