Review
Keynote
Drug metabolism in the paediatric population and in the elderly

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This review focuses on one of the key factors accounting for differences in drug/metabolite exposure in paediatric and elderly subjects compared with that of the adult population, that is, differences in drug metabolism (both qualitative and quantitative) and in particular differences due to changes in the activity and/or concentration of drug metabolizing enzymes. Important differences have been found in the paediatric population compared with adults for both phase I (e.g. CYP3A7 versus CYP3A4 and CYP1A2, reductive and hydrolytic enzymes) and phase II (e.g. glucuronosyltransferases) enzymes. In the elderly, some phase I enzymes (e.g. esterases) appear to be impaired. From the information collected thus far, it would appear that phase II reactions, though sometimes decreased, are not extensively affected by old age.

Section snippets

Drug metabolism

Metabolism renders drugs more water-soluble so that they can be easily excreted from the body after their desired effect has been exerted. This process occurs primarily in liver hepatocytes to generate metabolites that are inactive and relatively non-toxic; however, metabolites may occasionally be the source of toxic effects. For prodrugs, the parent drug is inactive but the metabolite is active. Drug metabolism mechanisms can be classified into phase I and phase II reactions, the former

Oxidative enzymes

A review paper on the ontogeny of human phase I oxidative enzymes has been recently written by Hines and McCarver [4].

Acetylation

Many drugs such as sulfamethazine, hydralazine, isoniazid, p-aminosalicylic acid, p-aminobenzoic acid, phenelzine or procainamide, as well as toxic agents are conjugated with an acetyl group. N-Acetyltransferase (NAT), a cytosolic enzyme, is widely distributed in mammalian tissues.

Paediatric population: The maturational development of acetylation reactions has been reviewed by Strolin Benedetti et al. [10]. Acetylation of p-aminobenzoic acid (NAT1) appears to be present in premature and

Conclusion

In this review, the key factors accounting for differences in drug/metabolite exposure, that is differences in drug metabolism (both qualitative and quantitative) at the extremes of age have been discussed. Numerous studies have demonstrated age-related changes in the pharmacokinetics of various drugs. However, it is difficult to differentiate the effect of age because of variations in enzyme activity from effects caused by other factors such as altered liver mass, liver blood flow and changes

Acknowledgement

The authors wish to thank Ms. M. Rovei for her assistance in the preparation of the manuscript.

MARGHERITA STROLIN BENEDETTI Margherita Strolin Benedetti (PhD Chemistry, University of Bologna) is the author of 450 publications in international journals, most in the area of biochemical pharmacology, enzymology, pharmacokinetics, drug metabolism and drug–drug interactions. She is presently Associate Director for Scientific Affairs in the Department of Non Clinical Development at UCB. She previously directed research groups in other international pharmaceutical companies, contributing to the

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  • Cited by (0)

    MARGHERITA STROLIN BENEDETTI Margherita Strolin Benedetti (PhD Chemistry, University of Bologna) is the author of 450 publications in international journals, most in the area of biochemical pharmacology, enzymology, pharmacokinetics, drug metabolism and drug–drug interactions. She is presently Associate Director for Scientific Affairs in the Department of Non Clinical Development at UCB. She previously directed research groups in other international pharmaceutical companies, contributing to the development of important drugs, and also worked as Research Assistant at the University of Geneva where she specialized in the study of drug metabolism with radiolabelled compounds.

    RHYS WHOMSLEY Rhys Whomsley (PhD Chemistry/Pharmacology, University of Wales) is the author of more than 30 publications in the area of drug metabolism and transport, pharmacokinetics and enzyme inhibition or induction. He has over 20 years experience in both scientific and regulatory aspects of drug development, leading teams in the pharma industry, contract research and at the University of Wales, where he focused on the development of steroidogenic enzyme inhibitors in the treatment of hormone-dependent cancers. He is currently Senior Principal Scientist Non-Clinical Development at UCB.

    MICHAEL CANNING Michael Canning (Veterinary Science, University of Bristol) is a veterinary pathologist by training and has over 17 years experience in non-clinical drug development and regulatory affairs with special interests in carcinogenicity and reproductive and juvenile toxicology. He is currently the Vice-president of Non-clinical Development at UCB having previously held positions in UK and continental Europe.

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