During human development impressive changes in drug disposition occur. An important
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 childhood. Therefore, an understanding
of the developmental regulation of different metabolic pathways, together with information
on the genetic determinants of drug metabolism, will increase the knowledge of inter-
and intraindividual variability in drug disposition during childhood. Conjugation
has historically received less attention than cytochrome P450 metabolism. An important
group of conjugation reactions are catalysed by the uridine 5'-diphosphate (UDP)-glucuronosyltransferases
(UGTs); to date at least 10 different UGT isoforms have been identified. The UGTs
are not only involved in the metabolism of many drugs [e.g. morphine, paracetamol
(acetaminophen)] but also capable of the biotransformation of important endogenous
substrates (e.g. bilirubin, ethinylestradiol) and several xenobiotics. Isoform specificity
for these substrates has, however, not been fully characterised. Serious adverse events
associated with chloramphenicol toxicity in the neonate have highlighted the importance
of developmental changes in UGT activity. However, isoform-specific differences preclude
the generalisation of a simple developmental pattern for UGT activity. UGT2B7 is the
only UGT isoform for which ontogeny has been characterised both in vitro and in vivo,
using morphine as the probe drug. However, no general developmental pattern for the
individual UGT isoforms which might be of value for the clinician is currently available.
Genetic polymorphisms have been identified for the UGT family. Not only for the UGT1A
gene, which reduces bilirubin glucuronidation, leading to genetic hyperbilirubinaemia
(the Crigler-Najjar and Gilbert's syndromes), but also for 3 other UGT isoforms. However,
the impact of these genetic differences on drug metabolism remains to be established
because of overlapping isoform specificity of the drugs studied, as well as a lack
of specific probe substrates to test the activity of individual UGT isoforms in relation
to these gene mutations. Clearly, an information gap exists regarding the developmental
and genetic aspects of UGT regulation and its potential impact on therapy. More research
is needed on the pharmacogenetics and ontogeny of the UGTs for effective translation
of scientific information into clinically applicable knowledge.