Bucolome N-Glucuronide Formation Species Differences and Identification of Human UDP-Glucuronosyltransferase Isoforms英文文献资料.docVIP

Pharmacology Pharmacy, 2011, 2, 361-369 361 doi:10.4236/pp.2011.24047 Published Online October 2011 (http://www.SciRP.org/journal/pp) Bucolome N-Glucuronide Formation: Species Differences and Identification of Human UDP-Glucuronosyltransferase Isoforms Humihisa Kanoh, Makiko Tada, Yoshihiro Uesawa, Kiminori Mohri * Clinical Pharmaceutics Laboratory, Department of Pharmacy and Health Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan. * Email: k-mohri@my-pharm.ac.jp Received August 4 , 2011; revised September 13 , 2011; accepted September 20 , 2011. th th th ABSTRACT The barbituric acid derivative bucolome (BCP) is a nonsteroidal anti-inflammatory drug. The present study investi- gated whether BCP N-glucuronide (BCP-NG, the primary metabolite of BCP) was produced in mammalian species other than rats, and attempted to identify the UDP-glucuronosyltransferase (UGT) isoform (s) responsible for forma- tion of BCP-NG in humans. BCP-NG was detected in all species tested. The results were as follows (pmol equivalent/ min/mg protein): rat, 479 ± 83; Mongolian gerbil, 378 ± 9; rabbit, 275 ± 26; guinea pig, 257 ± 10; human, 242 ± 18; hamster, 177 ± 22; and mouse, 167 ± 15. Since human liver microsomes formed BCP-NG, we investigated the metabo- lites of BCP excreted in the urine of a patient after oral administration of BCP (600 mg). BCP and BCP-NG were ex- creted in the urine at amounts of 2.9 mg (about 0.5% of the dose) and 14.4 mg (about 2.5% of the dose) over 12 hours. In order to identify the UGT isoforms involved in formation of BCP-NG in humans, we investigated BCP-NG formation by the microsomes of insect cells expressing each of twelve UGT isoforms (hUGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17).