Enantioselective effects of experimental diabetes mellitus on the metabolism of ibuprofen.
Diabetes mellitus is associated with numerous metabolic events that may influence the elimination of R- and S-ibuprofen and the inversion of R-ibuprofen. Short (3 days) and long (14 days) term experimental type I diabetes was induced in male Sprague-Dawley rats with streptozotocin, and genetically diabetic male Zucker rats were used as a model of type II diabetes. Isolated hepatocytes from long-term streptozotocin-treated rats exhibited significantly greater rate constants for ibuprofenyl-coenzyme A (CoA) formation (1.44 +/- 0.05 vs. 0.60 +/- 0.09 hr-1) and the elimination of R-ibuprofen (0.34 +/- 0.07 vs. 0.22 +/- 0.07 hr-1) relative to control (P < or = .05). These increases were consistent with significant induction of hepatic cytochrome P450 (1.14 +/- 0.45 vs. 0.54 +/- 0.10 nmol/mg protein) and an elevated hepatic free CoA content (313.4 +/- 48.5 vs. 172.9 +/- 38.6 nmol/g) relative to control (P < or = .05). In hepatocytes from type II diabetic rats there were significant reductions (P < or = .05) in the rate constants for ibuprofenyl-CoA formation (1.02 +/- 0.12 vs. 1.22 +/- 0.12 hr-1), R-ibuprofen elimination (0.21 +/- 0.06 vs. 0.34 +/- 0.10 hr-1) and S-ibuprofen elimination (0.41 +/- 0.07 vs. 0.73 +/- 0.11 hr-1) but no change in hepatic content of cytochrome P450 or CoA relative to control. The activity of ibuprofenyl-CoA synthetase in whole liver homogenate supplemented with ATP and CoA was not influenced by experimental diabetes. In both type I and type II diabetes there was a significantly greater exposure of hepatocytes to ibuprofenyl-CoA.(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.
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D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D007052:Ibuprofen / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D013237:Stereoisomerism; D013311:Streptozocin
D000894:Anti-Inflammatory Agents, Non-Steroidal; D013311:Streptozocin; D003577:Cytochrome P-450 Enzyme System; D007052:Ibuprofen