title: Conjugation-deconjugation cycling of diflunisal via beta-glucuronidase catalyzed hydrolysis of its acyl glucuronide in the rat.
abstract: The role of beta-glucuronidase catalyzed hydrolysis of glucuronides on the in vivo disposition kinetics of xenobiotics was studied in the rat. The metabolic disposition kinetics of diflunisal, a compound undergoing transformation to an acyl and phenyl glucuronide, were studied in rats under control conditions and following administration of D-glucaro-1,4-lactone, a potent and specific beta-glucuronidase inhibitor. D-glucaro-1,4-lactone treatment resulted in a significant decrease in beta-glucuronidase activity in plasma, urine, and hepatic microsomes. Total (i.e. urinary and biliary) recovery of the acyl glucuronide following i.v. injection of diflunisal (10 mg/kg) was significantly higher in D-glucaro-1,4-lactone treated rats (41 +/- 3%, n=6) compared to control rats (29 +/- 2%, n=6) whereas for diflunisal phenyl glucuronide this total recovery was very similar in both groups of rats (16.0 +/- 1.0% vs. 18.0 +/- 0.2%, n=6, respectively). The partial clearance of diflunisal associated with the formation of the acyl glucuronide was significantly higher in D-glucaro-1,4-lactone treated rats (0.413 +/- 0.024 ml/min/kg) compared to control animals (0.269 +/- 0.042 ml/min/kg). The partial clearance related to the formation of the phenyl glucuronide, on the contrary, was not significantly affected by D-glucaro-1,4-lactone treatment. These results shows that the in vivo glucuronidation of diflunisal to the acyl glucuronide, unlike diflunisal glucuronidation to the phenyl glucuronide, is subject to a futile conjugation-deconjugation cycle. Such futile cycling may have significant therapeutic and toxic implications.
authors.affiliation: Laboratory of Pharmacokinetics, School of Pharmacy, Catholic University of Louvain, Brussels, Belgium.
authors.forename: F M
authors.initials: FM
authors.lastname: Brunelle
authors.forename: R K
authors.initials: RK
authors.lastname: Verbeeck
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D002384:Catalysis; D004061:Diflunisal / Q000097:blood / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005937:Glucaric Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005965:Glucuronates / Q000378:metabolism*; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006868:Hydrolysis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D005965:Glucuronates; D004061:Diflunisal; C009194:saccharolactone; D005966:Glucuronidase; D005937:Glucaric Acid