title: Identification of the UDP-glucuronosyltransferase responsible for bucolome N-glucuronide formation in rats.
abstract: Bucolome N-glucuronide (BCP-NG), a major metabolite of bucolome (BCP), is the first unique N-glucuronide of barbituric acid derivatives to be reported. The purpose of the present study was to identify the UGT isoform(s) responsible for BCP-NG formation in rats. A pharmacokinetic study of BCP and the biliary excretion of BCP-NG was carried out in Wistar rats pretreated with phenobarbital (PB) (PB-pretreated rats), and the results were compared with those of Wistar rats not pretreated with PB (untreated rats). BCP N-glucuronidation activities were studied using hepatic microsomes prepared from Wistar rats pretreated with PB (primarily induces UGT1A1, 1A6 and 2B1) or with clofibric acid (CF, primarily induces UGT1A1 and 1A6), and from Gunn rats (deficiency of UGT1A family), and the results were compared with those of untreated rat microsomes.The plasma elimination clearance value of BCP in PB-pretreated rats was approximately 1.4 times greater than that of untreated rats. The cumulative amount (20.4 +/- 5.9 % of dose) of BCP-NG excreted in PB-pretreated rat bile was approximately 1.5-fold higher than that (13.4 +/- 2.5% of dose) in untreated rat bile, and BCP-NG (5.9 +/- 3.0%) and BCP (3.0 +/- 2.6%) excreted in PB-pretreated rat urine were approximately 3.0- and 1.8-fold higher than those in untreated rat urine (BCP-NG: 2.0 +/- 1.4%; BCP: 1.7 +/- 1.3%), respectively.BCP N-glucuronidation activities in PB- and CF-pretreated microsomes were approximately 1.5- and 1.6-fold higher than in untreated microsomes, respectively. BCP N-glucuronidation activity in the microsomes of Gunn rats was markedly reduced by approximately 8.5% in untreated rat microsomes. The results suggest that UGT 1A1 is primarily responsible for BCP N-glucuronide formation in rats.
authors.affiliation: Clinical Pharmaceutics Laboratory, Department of Pharmacy and Health Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kanoh
authors.forename: K
authors.initials: K
authors.lastname: Okada
authors.forename: K
authors.initials: K
authors.lastname: Mohri
mesh_terms: D000818:Animals; D001463:Barbiturates / Q000378:metabolism* / Q000493:pharmacokinetics; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics / Q000494:pharmacology; D007202:Indicators and Reagents; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010424:Pentobarbital / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011911:Rats, Gunn; D017208:Rats, Wistar; D012015:Reference Standards
chemical_list: D001463:Barbiturates; D020719:Glucuronides; D006993:Hypnotics and Sedatives; D007202:Indicators and Reagents; C046662:bucolome N-glucuronide; D014453:Glucuronosyltransferase; D010424:Pentobarbital