Pharmacokinetic data reported during the past two decades clearly demonstrate that development markedly influences the absorption, distribution, excretion, and metabolism of many xenobiotics. With respect to many of the processes that govern drug metabolism, genetically determined events that control the affinity or capacity of a drug or toxicant substrate for the enzyme(s) responsible for its biotransformation seem to vary as a consequence of development. Despite the fact that developmental differences in drug metabolism often produce definable “patterns” in drug clearance that may enable pharmacokinetic description of patient subpopulations within the pediatric age group,<sup>34 Kauffman R.E., Kearns G.L. Pharmacokinetic studies in pediatric patients: Clinical and ethical considerations Clin Pharmacokin 1992 ;  23 : 10

Cliccare qui per andare alla sezione Riferimenti</sup> the relationship between age-dependent changes in drug metabolism and the myriad of biochemical events that occur and change in developing humans remains largely uncharacterized.

Although development represents a continuum of biologic events that enable adaptation, somatic growth, and eventually reproduction, its impact on the metabolism of drugs depends on the acquisition of specific organ function via organogenesis (especially in preterm infants) and recruitment of functional “units” within an organ. With regard to organs that possess the metabolic machinery necessary to biotransform xenobiotics, the underlying genetic determinants that regulate drug metabolism are influenced by both the developmental and environmental factors that can alter the expression of activity for a given drug-metabolizing enzyme.<sup>36 Kearns G.L. Pharmacogenetics and development: Are infants and children at increased risk for adverse outcomes? Curr Opin Pediatr 1995 ;  7 : 220

Cliccare qui per andare alla sezione Riferimenti</sup> These multifactorial determinants result in developmentally dependent changes in drug metabolism that may influence the therapeutic response to alter the expected (or desired) dose-concentration versus effect relationship, which can produce either drug toxicity or lack of efficacy.<sup>56 May G. Genetic differences in drug disposition J Clin Pharmacol 1994 ;  34 : 881

Cliccare qui per andare alla sezione Riferimenti</sup> Lack of proper characterization of the interface between pharmacogenetics and developmental changes in drug metabolizing enzyme activity frequently leaves pediatric practitioners with a therapeutic dilemma: the drug and dose selection is frequently performed by “guided empiricism,” in which developmental physiology and clinical pharmacology are joined in a decision-making process that lacks sufficient power to accurately predict variability in pharmacokinetics and pharmacodynamics.<sup>38 Kearns G.L., van den Anker J.N. Drug metabolism in the neonate and young infant Intensive Care in Childhood: A Challenge to the Future (Update in Intensive Care and Emergency Medicine; vol 25) New York: Springer-Verlag (1996).  385

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The goal of rational drug therapy in infants, children, and adolescents is to produce a desired pharmacologic response in an acceptable and predictable manner while minimizing the occurrence of undesired events. This goal requires not only an increasing awareness of the need to individualize drug dosing but also most importantly a recognition of those factors contributing to the interindividual and intraindividual variability in drug disposition and response. The purpose of this article is to acquaint clinicians with the ontogeny of important drug metabolizing enzymes during childhood by briefly reviewing the interface between pharmacogenetics, developmental physiology, and pharmacokinetics. This article focuses specifically on the contribution of genetic determinants of drug metabolism or biotransformation, as modified by developmental processes, to the heterogeneity observed in the pediatric population. Within this context, relevant examples of clinical consequences of such variability on pediatric pharmacotherapy are presented and discussed. For a more generalized and in-depth discussion of drug metabolism and pharmacogenetics, the reader should consult several recent reviews pertaining to these topics.<sup>27 Gonzalez F.J., Idle J.R. Pharmacokinetic phenotyping and genotyping: Present status and future potential Clin Pharmacokin 1994 ;  26 : 59  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 36 Kearns G.L. Pharmacogenetics and development: Are infants and children at increased risk for adverse outcomes? Curr Opin Pediatr 1995 ;  7 : 220

Cliccare qui per andare alla sezione Riferimenti, 51 Leeder J.S., Okey A.B. Cytochromes P450 and liver injury Drug-Induced Hepatotoxicity. (Handbook of Experimental Pharmacology; vol 121) Berlin: Springer (1996).  119

Cliccare qui per andare alla sezione Riferimenti, 71 Parkinson A. Biotransformation of Xenobiotics Casarett & Doull's Toxicology. The Basic Science of Poisons New York: McGraw-Hill (1996).  113

Cliccare qui per andare alla sezione Riferimenti, 106 Wrighton S.A., Stevens J.C. The human hepatic cytochromes P450 involved in drug metabolism CRC Crit Rev Toxicol 1992 ;  22 : 1  [cross-ref]

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