Abstract
UDP-glucuronosyltransferases (UGTs) are critical for the metabolism and clearance of drugs, chemicals, and hormones. The development of UGT1A1 and 1A6 was studied in 50 pediatric liver samples using bilirubin, serotonin activity assays, and Western blot as well as pharmacokinetic scaling. UGT activity developed age dependently in pediatric liver. Maximal activity of 0.7690 nmol · min · (-1) mg protein(-1) was observed for UGT1A1 at 3.8 months. For UGT1A6, activity matured at 14 months (4.737 nmol · min · (-1)mg protein(-1)). Protein expression was not age-dependent, and activities did not correlate to protein levels for either enzyme. The in vitro activities were used to calculate normalized hepatic clearances using both allometric scaling and a physiologically based pharmacokinetic model. For UGT1A1, allometry predicted normalized adult clearances of 0.0070 l · h(-1) · kg(-1) at 3.0 (well stirred) and 2.8 years (parallel tube), whereas the Simcyp model showed normalized clearances of 0.0079 l · h(-1) · kg(-1) at 2.6 (well stirred) and 2.5 years (parallel tube). For UGT1A6, only the Simcyp well stirred model converged at 0.3524 l · h(-1) · kg(-1) at 12.6 months. These data imply independent regulation of UGT1A1 and 1A6 where activity has matured after 6 months to 1 year. Total hepatic clearance of substances mediated by these enzymes may mature concurrently or take longer because of other physiological factors. Late development of UGT enzymes may contribute to chemical, drug, and environmental toxicity.