Conjugation-deconjugation cycling of diflunisal via β-glucuronidase catalyzed hydrolysis of its acyl glucuronide in the rat

doi:10.1016/S0024-3205(97)00166-5

Life Sciences

Volume 60, Issue 22, 25 April 1997, Pages 2013-2021

https://doi.org/10.1016/S0024-3205(97)00166-5 Get rights and content

Abstract

The role of β-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 β-glucuronidase inhibitor. D-glucaro-1,4-lactone treatment resulted in a significant decrease in β-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.

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Citation Excerpt :
UDPGA formed from glucose-1-phosphate has been hypothesized to be converted to glucuronate either through a series of dephosphorylation steps [9] or through the obligatory formation of a xenobiotic glucuronide prior to its chemically induced or β-glucuronidase-catalyzed deglucuronidation [10]. The latter pathway would be most pertinent to labile acyl glucuronides such as the non-steroidal anti-inflammatory drug, diflunisal, which has been shown to undergo β-glucuronidase-mediated hydrolysis rapidly, but would be an unlikely pathway for chemicals with primary amines or hydroxyl groups. [11]. Ascorbate synthesis caused by GSH depletion in our system was indeed derived from glycogenolysis because both hepatocytes from fasted rats and fructose treated hepatocytes were unable to synthesize ascorbate in response to GSH conjugation.
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Conjugation-deconjugation cycling of diflunisal via β-glucuronidase catalyzed hydrolysis of its acyl glucuronide in the rat

Abstract

Life Sci.

J. Biol. Chem.

Biochem. Pharm.

Biochem. Pharmacol.

Lancet

Lancet

J. Biol. Chem.

Biochem. Pharmacol.

Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity

Biochem.J.

Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity

Hepatology

Chem. Pharm. Bull.