Identification of a Novel N -Carbamoyl Glucuronide: In Vitro, In Vivo, and Mechanistic Studies

]BMS-690514 to rats and dogs, the majority of the radioactive dose (61-71%) was recovered in the feces, whereas 18 to 20% was eliminated in urine. In bile duct-cannulated rats, 83 and 17% of the administered radioactivity was recovered in the bile and urine, respectively, suggesting that biliary secretion was a major route for the elimination of BMS-690514-derived radioactivity in rats.The parent compound underwent extensive metabolism in both species, with <12% of the administered radioactivity recovered as BMS-690514 in the excreta samples. Metabolite profiles in plasma were qualitatively similar in rats, rabbits, and dogs. Unchanged BMS-690514 was a prominent drug-related component in the plasma profiles from all the species. However, multiple metabolites contributed significantly to the circulating radioactivity, particularly for rabbit and dog, in which metabolites comprised 73 to 93% of the area under the time curve (0-8 h). Circulating metabolites included M6, a direct Oglucuronide conjugate; M1, a hydroxylated metabolite; and glucuronide conjugates of hydroxylated and O-demethylated metabolites. Overall, the results from these studies suggested that BMS-690514 was well absorbed and highly metabolized through multiple pathways in these preclinical species.

Section: Disposition Of Bms-690514 In Rats Dogs and Rabbitsmentioning

confidence: 85%

Metabolism and Disposition of [¹⁴C]BMS-690514 after Oral Administration to Rats, Rabbits, and Dogs

Hong

Su²,

Sun³

et al. 2010

“…5. Mechanistic studies with 13 C-labeled CO 2 suggest that formation of N-carbamoyl glucuronide of compound 1 was driven by exogenous CO 2 in equilibrium with CO 2 dissolved in the buffer in rat liver microsomes (Gunduz et al, 2010). Carbamic acids can convert back to parent moieties upon hydrolysis (Tremaine et al, 1989) or even during sample preparation.…”

Section: Carbamoyl Glucuronidesmentioning

confidence: 99%

Unusual Glucuronides

Argikar¹

2012

Self Cite

ABSTRACT:Glucuronidation reaction is catalyzed by mammalian uridine diphosphoglucuronosyl transferases by using uridine diphosphoglucuronic acid as a cosubstrate. Conjugation of glucuronic acid to nucleophilic functional groups in chemical entities results in formation of glucuronides. As anticipated, a number of nucleophilic functional groups such as hydroxyl, phenolic, acyl, primary secondary and tertiary amino, etc. in a diverse set of chemical compounds are known to form the corresponding glucuronides. Glucuronides have been reported to be formed at carbon atoms, selenium atoms, and upon N-carbamoylation of primary and secondary amino groups. Glucuronides are also believed to be the end products of metabolism. However, there are examples where glucuronidation results in further oxidative or conjugative biotransformation reactions. The objective of this review is to highlight unusual glucuronide conjugates. Diglucuronide conjugates reported in the literature fall under two distinct categories. Use of prefixes such as "bis" versus "di" has been previously proposed for separating the two types of diglucuronides. In spite of this, literature reports for diconjugative glucuronide metabolites reflect interchangeable use of "bisglucuronides" and "diglucuronides." Furthermore, the application of such prefixes does not adhere to recommendations of International Union of Pure and Applied Chemistry nomenclature for substituent groups. Therefore, an effort is made in this review to document the historic reports for diglucuronides into two distinct types for sake of clarity and to allow differentiation between the two types of diconjugative metabolites. Overall, this commentary centers on unusual glucuronide metabolites that result from conjugation at uncommon functional groups, glucuronides undergoing ensuing oxidative or conjugative metabolic transformations. Structural and mechanistic aspects are also discussed.

“…Among these three UGTs, UGT2B7 was shown to be the only UGT involved in N-carbamoyl glucuronidation of varenicline (Obach et al, 2006) and was the major UGT for sertraline ; both of these drugs are secondary amines. In contrast, UGT2B7 plays a very minor role in N-carbamoyl glucuronidation of a primary amine, dipeptidyl peptidase-4 inhibitor (Gunduz et al, 2010). We observed, for the first time, that UGT2B15 and UGT2B17, in addition to UGT2B7, are involved in N-carbamoyl glucuronidation of a secondary amine, lorcaserin.…”

Section: Human Ugt Involved In Lorcaserin N-carbamoyl Glucuronidationmentioning

confidence: 65%

“…Although a number of publications investigated its possible mechanism (Schaefer, 1992(Schaefer, , 2006Shaffer et al, 2005), few studies report the identification of UGT enzymes that catalyze the N-carbamoyl glucuronidation pathway (Obach et al, , 2006Gunduz et al, 2010). In this study, we identified the human UGT enzymes involved in N-carbamoyl glucuronidation of lorcaserin.…”

Section: Discussionmentioning

confidence: 90%

“…Another class of glucuronidation reactions, the N-carbamoyl glucuronidation of primary and secondary amines, is being reported more frequently in the literature (Straub et al, 1988;Tremaine et al, 1989;Schaefer, 1992Schaefer, , 2006. In recent years, drugs such as sertraline , varenicline (Obach et al, 2006), and a novel dipeptidyl peptidase-4 inhibitor (Gunduz et al, 2010) were shown to form N-carbamoyl glucuronide metabolites by UGT enzymes. Herein, N-carbamoyl glucuronidation of lorcaserin by human UGTs is reported.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of Human UDP-Glucuronosyltransferases Involved in N-Carbamoyl Glucuronidation of Lorcaserin

Sadeque

Usmani²,

Palamar³

et al. 2012

ABSTRACT:Lorcaserin, a selective serotonin 5-HT 2C receptor agonist, is a weight management agent in clinical development. Lorcaserin Ncarbamoyl glucuronidation governs the predominant excretory pathway of lorcaserin in humans. Human UDP-glucuronosyltransferases (UGTs) responsible for lorcaserin N-carbamoyl glucuronidation are identified herein. Lorcaserin N-carbamoyl glucuronide formation was characterized by the following approaches: metabolic screening using human tissues (liver, kidney, intestine, and lung) and recombinant enzymes, kinetic analyses, and inhibition studies. Whereas microsomes from all human tissues studied herein were found to be catalytically active for lorcaserin N-carbamoyl glucuronidation, liver microsomes were the most efficient. With recombinant UGT enzymes, lorcaserin N-carbamoyl glucuronidation was predominantly catalyzed by three UGT2Bs (UGT2B7, UGT2B15, and UGT2B17), whereas two UGT1As (UGT1A6 and UGT1A9) played a minor role. UGT2B15 was most efficient, with an apparent K m value of 51.6 ؎ 1.9 M and V max value of 237.4 ؎ 2.8 pmol/mg protein/min. The rank order of catalytic efficiency of human UGT enzymes for lorcaserin N-carbamoyl glucuronidation was UGT2B15 > UGT2B7 > UGT2B17 > UGT1A9 > UGT1A6. Inhibition of lorcaserin N-carbamoyl glucuronidation activities of UGT2B7, UGT2B15, and UGT2B17 in human liver microsomes by mefenamic acid, bisphenol A, and eugenol further substantiated the involvement of these UGT2B isoforms. In conclusion, multiple human UGT enzymes catalyze N-carbamoyl glucuronidation of lorcaserin; therefore, it is unlikely that inhibition of any one of these UGT activities will lead to significant inhibition of the lorcaserin N-carbamoyl glucuronidation pathway. Thus, the potential for drug-drug interaction by concomitant administration of a drug(s) that is metabolized by any of these UGTs is remote.