Glucuronidation of R- and S-ketoprofen, acetaminophen, and diflunisal by liver microsomes of adjuvant-induced arthritic rats.
The effect of adjuvant-induced arthritis on hepatic microsomal glucuronidation was studied in the rat. Arthritis was induced by injection of Mycobacterium butyricum suspended in liquid paraffin. Vmax and the Michaelis-Menten constant values for the in vitro glucuronidation of R- and S-ketoprofen, acetaminophen, and diflunisal by liver microsomes obtained from control and adjuvant-induced arthritic rats were compared. In addition, uridine 5'-diphosphate-glucuronosyltransferase activity toward bilirubin and p-nitrophenol, as well as levels of cytochrome P-450 and beta-glucuronidase were determined in these microsomal preparations. Adjuvant-induced arthritis resulted in a significant reduction in hepatic cytochrome P-450 levels and in p-nitrophenol glucuronidation (5.65 +/- 0.40 versus 2.58 +/- 0.27 micromol.min/mg protein in control and arthritic rats, respectively, mean +/- S.E.M.). Glucuronidation of bilirubin and beta-glucuronidase activities in liver microsomes and in plasma were not affected by adjuvant-induced arthritis. Vmax (nmol/min/mg protein) for the formation of R-ketoprofen glucuronide, S-ketoprofen glucuronide, diflunisal phenolic glucuronide, and diflunisal acyl glucuronide was significantly decreased in arthritic rats (0.68 +/- 0.10, 0.77 +/- 0. 12, 0.044 +/- 0.005, 0.26 +/- 0.03, respectively) compared with control rats (1.45 +/- 0.04, 1.60 +/- 0.04, 0.087 +/- 0.008, 0.46 +/- 0.04, respectively). Glucuronidation of p-nitrophenol, ketoprofen and diflunisal, substrates which seem to be at least partly glucuronidated in the rat by isoenzymes of the UGT2B subfamily, was impaired in adjuvant-induced arthritis. Glucuronidation of bilirubin and acetaminophen, substrates of UGT1- isoenzymes, was not affected by adjuvant-induced arthritis. It seems, therefore, that adjuvant-induced arthritis in the rat leads to impaired glucuronidation of substrates of the UGT2B subfamily.
Meunier
C J
CJ
Pharmacokinetics and Drug Metabolism Laboratory, School of Pharmacy, Catholic University of Louvain, Brussels, Belgium.
Verbeeck
R K
RK
D000082:Acetaminophen / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004061:Diflunisal / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism*; D007660:Ketoprofen / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005965:Glucuronates; D000082:Acetaminophen; D004061:Diflunisal; D007660:Ketoprofen