title: Differential effects of phenobarbital on ester and ether glucuronidation of diflunisal in rats.
abstract: The relative contribution of ether and ester glucuronidation to diflunisal metabolism was assessed by studying the effects of enzyme inducers, phenobarbital (PB), 3-methylcholanthrene (3-MC) and beta-naphthoflavone (BNF). Treatment with either PB, 3-MC or BNF increased markedly the unbound intrinsic clearance of diflunisal. Saline-treated control rats showed a greater unbound intrinsic clearance of diflunisal than oil-treated controls indicating that repetitive treatment with oil had an effect on enzyme activity. Treatment with 3-MC and BNF appeared to cause a decrease in the biliary clearance of ether and ester glucuronide, but PB had little effect on the biliary clearance of glucuronides. Rats pretreated with PB showed a 3-fold increase in the fractional metabolite formation clearance of ether glucuronide and a 2-fold increase in the fractional metabolite formation clearance of ester glucuronide, suggesting differential effects of PB on ester and ether glucuronidation. A similar trend, but to a smaller extent, was also observed for 3-MC- and BNF-treated rats. These results suggest the possibility of selective induction of multiple forms of UDP-glucuronyltransferase involved in metabolism of diflunisal.
authors: Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania.
authors: J H
authors: JH
authors: Lin
authors: I W
authors: IW
authors: Chen
authors: E H
authors: EH
authors: Ulm
authors: D E
authors: DE
authors: Duggan
mesh_terms: D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D001646:Bile / Q000378:metabolism; D004061:Diflunisal / Q000378:metabolism*; D004952:Esters / Q000378:metabolism; D004987:Ethers / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008297:Male; D008657:Metabolic Clearance Rate; D008748:Methylcholanthrene / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D012459:Salicylates / Q000378:metabolism*; D019324:beta-Naphthoflavone
chemical_list: D001571:Benzoflavones; D004952:Esters; D004987:Ethers; D005965:Glucuronates; D012459:Salicylates; D008748:Methylcholanthrene; D019324:beta-Naphthoflavone; D004061:Diflunisal; D010634:Phenobarbital