Use of cloned and expressed human UDP-glucuronosyltransferases for the assessment of human drug conjugation and identification of potential drug interactions

Glucuronidation is an important pathway for human drug metabolism. Four clo ned and expressed human UDP-glucuronosyltransferases (UGT1A1, UGT1A6, UGT1A 9, and UGT2B15) were used to screen a series of three potential drug substr ates differing only in position of the phenol moiety. The meta and para phe nols, UK-156,037 and UK-157,147, were found to be substrates for UGT1A1 wit h K-m values of 256 and 105 muM, respectively. The ortho phenol UK-157,261 was glucuronidated predominantly by UGT1A9 with a K-m of 45 muM. The latter K-m compares favorably with the known UGT1A9 substrate propofol (K-m = 200 muM). In a series of competition experiments, UK-157,261 was shown to inhi bit the glucuronidation of propofol by UGT1A9 with a K-i value of 65 muM. T his result indicates that even the most potent of these compounds is extrem ely unlikely to interact in the clinic with the glucuronidation of propofol . This study shows the utility of the expressed human UDP-glucuronosyltrans ferases in determining substrate structure-activity relationships and poten tial drug-drug interactions.