Glucuronidation in humans - Pharmacogenetic and developmental aspects

Citation
Sn. De Wildt et al., Glucuronidation in humans - Pharmacogenetic and developmental aspects, CLIN PHARMA, 36(6), 1999, pp. 439-452
Citations number
103
Categorie Soggetti
Pharmacology,"Pharmacology & Toxicology
Journal title
CLINICAL PHARMACOKINETICS
ISSN journal
03125963 → ACNP
Volume
36
Issue
6
Year of publication
1999
Pages
439 - 452
Database
ISI
SICI code
0312-5963(199906)36:6<439:GIH-PA>2.0.ZU;2-#
Abstract
During human development impressive changes in drug disposition occur. An i mportant determinant of drug clearance is metabolism something that is not only determined by ontogenic regulation but also by genetic processes which add to the variability of drug metabolism during different stages of child hood. Therefore, an understanding of the developmental regulation of differ ent metabolic pathways, together with information on the genetic determinan ts of drug metabolism, will increase the knowledge of inter- and intraindiv idual Variability in drug disposition during childhood. Conjugation has historically received less attention than cytochrome P450 m etabolism. An important group of conjugation reactions are catalysed by the uridine 5'-diphosphate (UDP)-glucuronosyltransferases (UGTs); to date at l east 10 different UGT isoforms have been identified. The UGTs are not only involved in the metabolism of many drugs [e.g. morphine, paracetamol (aceta minophen)] but also capable of the biotransformation of important endogenou s substrates (e.g. bilirubin, ethinylestradiol) and several xenobiotics. Is oform specificity for these substrates has, however, not been fully charact erised. Serious adverse events associated with chloramphenicol toxicity in the neon ate have highlighted the importance of developmental changes in UGT activit y. However, isoform-specific differences preclude the generalisation of a s imple developmental pattern for UGT activity. UGT2B7 is the only UGT isofor m for which ontogeny has been characterised both in vitro and in vivo, usin g morphine as the probe drug. However, no general developmental pattern for the individual UGT isoforms which might be of value for the clinician is c urrently available. Genetic polymorphisms have been identified for the UGT family. Not only for the UGT1A gene, which reduces bilirubin glucuronidation, leading to geneti c hyperbilirubinaemia (the Crigler-Najjar and Gilbert's syndromes), but als o for 3 other UGT isoforms. However, the impact of these genetic difference s on drug metabolism remains to be established because of overlapping isofo rm specificity of the drugs studied, as well as a lack of specific probe su bstrates to test the activity of individual UGT isoforms in relation to the se gene mutations. Clearly, an information gap exists regarding the developmental and genetic aspects of UGT regulation and its potential impact on therapy. More researc h is needed on the pharmacogenetics and ontogeny of the UGTs for effective translation of scientific information into clinically applicable knowledge.