TY - JOUR T1 - DIFFERENCES IN THE PHARMACOKINETICS OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR AGONISTS IN GENETICALLY OBESE ZUCKER AND SPRAGUE-DAWLEY RATS: IMPLICATIONS OF DECREASED GLUCURONIDATION IN OBESE ZUCKER RATS JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 909 LP - 914 VL - 32 IS - 9 AU - Mi-Sook Kim AU - Sui Wang AU - Zhongzhou Shen AU - Christopher J. Kochansky AU - John R. Strauss AU - Ronald B. Franklin AU - Stella H. Vincent Y1 - 2004/09/01 UR - http://dmd.aspetjournals.org/content/32/9/909.abstract N2 - Genetically obese Zucker rats exhibit symptoms similar to those of obese patients with insulin-resistance or Type II diabetes; therefore, they have been used as a genetic model to study obesity, as well as a pharmacological model for the discovery of new drugs for the treatment of Type II diabetes and hyperlipidemia. In the present study, we compared the pharmacokinetics of two novel peroxisome proliferator-activated receptor (PPAR) agonists, MRL-I [(2R)-7-[3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy]-2-ethyl-3,4-dihydro-2H-benzopyran-2-carboxylic acid] and MRL-II [(2R)-7-[3-[2-chloro-4-(2,2,2-trifluoroethoxy)phenoxy]propoxy]-3,4-dihydro-2-methyl-2H-benzopyran-2-carboxylic acid], in obese Zucker and lean Sprague-Dawley rats following a single intravenous administration. The plasma clearance of both MRL-I and MRL-II was significantly lower in obese Zucker rats (4- and 2-fold, respectively) compared with Sprague-Dawley rats, but without any significant change in the volume of distribution, which resulted in a dramatic increase in the half-life (7- and 3-fold, respectively). The reversible in vitro plasma protein binding of [14C]MRL-I and [14C]MRL-II was comparable in the two strains, ∼96% bound. The expression levels of uridine diphosphate-glucuronosyltransferases 1A1, 1A6, 2B1, and CYP2C11 and 3A1 mRNA in liver were lower (30-50%) in Zucker compared with Sprague-Dawley rats, as were the liver glutathione S-transferases (70%), quinone reductase (30%), organic anion-transporting protein 2 (80%), and multidrug resistance-associated protein 2 (Mrp2) (50%) mRNA levels. However, Mrp3 mRNA levels were similar in both strains. Consistent with these observations, the intrinsic clearance (CLint), calculated from the Vmax/Km of glucuronidation of [14C]MRL-I and [14C]MRL-II in liver microsomes, was ∼2-fold lower in obese Zucker rats; the Km values were comparable in the two strains for both compounds. In conclusion, differences in the pharmacokinetics of two novel PPAR agonists, both cleared, predominantly, by conjugation, were evident in genetically obese Zucker rats compared with Sprague-Dawley rats. These differences were consistent with changes in the mRNA levels of hepatic drug-metabolizing enzymes and transporters. This information should be considered when comparing pharmacokinetic and efficacious doses in the obese Zucker rats, used as a pharmacological model, with those in Sprague-Dawley rats, which are used widely for drug metabolism and toxicology studies. The American Society for Pharmacology and Experimental Therapeutics ER -