Abstract
The barbituric acid derivative bucolome (BCP) is a nonsteroidal anti-inflammatory drug. The present study investigated 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 formation 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 metabolites of BCP excreted in the urine of a patient after oral administration of BCP (600 mg). BCP and BCP-NG were excreted 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). As a result, BCP-NG formation (pmol equivalents/min/mg protein) was observed with microsomes expressing hUGT1A1 (142), 1A3 (196), 1A4 (8), 1A7 (8), 1A8 (66), 1A9 (38), 1A10 (9), 2B4 (7) and 2B7 (16). In particular, the activity of hUGT1A1 and 1A3 was high. These results suggest that the UGT isoforms responsible for formation of BCP-NG exist in various mammalian species, including humans, and that the UGT 1A family is primarily responsible for BCP N-glucuronide formation in humans.
Highlights
Glucuronic acid conjugation is an enzymatic reaction catalyzed by UDP-glucuronosyltransferase (UGT; EC 2.4.1.17), and it is one of the most important reactions in phase II drug metabolism
The activity of hUGT1A1 and 1A3 was high. These results suggest that the UGT isoforms responsible for formation of BCP-NG exist in various mammalian species, including humans, and that the UGT 1A family is primarily responsible for BCP N-glucuronide formation in humans
There have been a few reports of N-glucosides and N-glucuronides in which glucose or glucuronic acid is directly attached to a nitrogen (N) atom in the pyrimidine skelton of barbiturates
Summary
Glucuronic acid conjugation is an enzymatic reaction catalyzed by UDP-glucuronosyltransferase (UGT; EC 2.4.1.17), and it is one of the most important reactions in phase II drug metabolism. UGT is widely present in many species from bacteria to humans, and glucuronic acid conjugation is estimated to account for about 35% of phase II drug metabolism [1]. Bucolome (BCP, Figure 1) is a barbituric acid derivative nonsteroidal anti-inflammatory drug that exhibits analgesic and anti-inflammatory actions without having sedative or hypnotic effects, unlike many barbiturates. It has been used for the treatment of rheumatoid arthritis [2]. BCP is used for various purposes, as noted above, its metabolic pathway and the enzymes involved in humans have not been evaluated in detail, with only old references being available [5,8,9,10,11]
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