PT  - JOURNAL ARTICLE
AU  - Ji Y. Zhang
AU  - Jenny Zhan
AU  - Chyung S. Cook
AU  - Robert M. Ings
AU  - Alan P. Breau
TI  - Involvement of Human UGT2B7 and 2B15 in Rofecoxib Metabolism
AID  - 10.1124/dmd.31.5.652
DP  - 2003 May 01
TA  - Drug Metabolism and Disposition
PG  - 652--658
VI  - 31
IP  - 5
4099  - http://dmd.aspetjournals.org/content/31/5/652.short
4100  - http://dmd.aspetjournals.org/content/31/5/652.full
SO  - Drug Metab Dispos2003 May 01; 31
AB  - O-Glucuronidation of 5-hydroxyrofecoxib is the major biotransformation pathway of rofecoxib in human, rat, and dog. The glucuronide conjugate is also involved in the reversible metabolism of rofecoxib in rat and human. Atypical bimodal phenomena were observed in their plasma concentration-time curves with a large variability among different human subjects. It is unclear which family members of human UDP-glucuronosyltransferases (UGT) are involved in the formation of the glucuronide. O-Glucuronidation of 5-hydroxyrofecoxib by human liver microsomes and eight cDNA-expressed human UGT isoforms were investigated. Human liver microsomes formed 5-hydroxyrofecoxib glucuronide with apparent Vmax value of 1736 pmol/min/mg of protein and Km value of 44.2 μM. Eight individual cDNA-expressed human UGT isozymes (1A1, 1A3, 1A4, 1A6, 1A8, 1A9, 2B7, and 2B15) were evaluated for glucuronidation of 5-hydroxyrofecoxib. Among them UGT2B15 exhibited the highest metabolism rate with apparent Vmax value of 286 pmol/min/mg of protein and Km value of 16.1 μM, whereas UGT2B7 showed apparentVmax value of 47.1 pmol/min/mg of protein and Km value of 41.6 μM. These results indicated that human UGT2B15 has the highest level of activity for catalyzing the glucuronidation of 5-hydroxyrofecoxib. Because polymorphisms have been identified in human UGT2B7, 2B15 genes andO-glucuronidation of 5-hydroxyrofecoxib plays a major role in biotransformation of rofecoxib, it is possible that human UGT2B7 and 2B15 polymorphisms for O-glucuronidation of 5-hydroxyrofecoxib are responsible for the high variability in bimodal patterns in human plasma concentration-time curves. The American Society for Pharmacology and Experimental Therapeutics