Ontogeny of Hepatic Glucuronidation; Methods and Results

Elke      H.J. Krekels; Meindert      Danhof; Dick      Tibboel; Catherijne      A.J. Knibbe

Abstract

The onset and maturation, or so-called ontogeny, of hepatic glucuronidation is important for the clearance of a number of drugs in children. The current review discusses methods for studying the ontogeny of liver enzyme systems and specifically focuses on the results obtained with these methods for uridine 5’-diphosphate glucuronosyltransferases (UGTs). The number of contributing components in the biological system increases in going from mRNA transcription, to enzyme expression, in vitro enzyme activity, and in vivo glucuronidation clearance. This may result in different conclusions on UGT ontogeny when different methods are used. Various metrics to quantify glucuronidation activity, like linear or allometric scaling based on bodyweight, further disperse the conclusions on UGT ontogeny. Generally, it can be concluded that the onset of UGT expression and activity occurs after 20 weeks of gestation with a boost in expression and activity occurring in the first weeks of life. Maturation rates vary between the UGTs, but may well extend beyond the age of two years. Compared to adults, absolute doses of drugs eliminated via glucuronidation should be reduced in children. However, since the UGT isoenzymes mature differently, since substrate specificities are overlapping and since many external factors influence drug glucuronidation, it is not possible to derive general dosing recommendations for the pediatric population for these drugs. This can be improved by obtaining system specific information on each UGT isoenzyme on the basis of validated in vivo models that describe the ontogeny of glucuronidation and the influence of other patient characteristics like genetic polymorphisms and co-morbidities on the (intrinsic) clearance of isoenzyme specific probe drugs.

Keywords: Glucuronidation, hepatic metabolism, maturation, ontogeny, pediatrics, UGT, isoenzymes, probe drugs, polymorphisms, mRNA, glutathione