title: Difference in the Pharmacokinetics and Hepatic Metabolism of Antidiabetic Drugs in Zucker Diabetic Fatty and Sprague-Dawley Rats.
abstract: The Zucker diabetic fatty (ZDF) rat, an inbred strain of obese Zucker fatty rat, develops early onset of insulin resistance and displays hyperglycemia and hyperlipidemia. The phenotypic changes resemble human type 2 diabetes associated with obesity and therefore the strain is used as a pharmacological model for type 2 diabetes. The aim of the current study was to compare the pharmacokinetics and hepatic metabolism in male ZDF and Sprague-Dawley (SD) rats of five antidiabetic drugs that are known to be cleared via various mechanisms. Among the drugs examined, metformin, cleared through renal excretion, and rosiglitazone, metabolized by hepatic cytochrome P450 2C, did not exhibit differences in the plasma clearance in ZDF and SD rats. In contrast, glibenclamide, metabolized by hepatic CYP3A, canagliflozin, metabolized mainly by UDP-glucuronosyltransferases (UGT), and troglitazone, metabolized by sulfotransferase and UGT, exhibited significantly lower plasma clearance in ZDF than in SD rats after a single intravenous administration. To elucidate the mechanisms for the difference in the drug clearance, studies were performed to characterize the activity of hepatic drug-metabolizing enzymes using liver S9 fractions from the two strains. The results revealed that the activity for CYP3A and UGT was decreased in ZDF rats using the probe substrates, and decreased unbound intrinsic clearance in vitro for glibenclamide, canagliflozin, and troglitazone was consistent with lower plasma clearance in vivo. The difference in pharmacokinetics of these two strains may complicate pharmacokinetic/pharmacodynamic correlations, given that ZDF is used as a pharmacological model, and SD rat as the pharmacokinetics and toxicology strain.
authors.affiliation: Drug Disposition (X.Z., L.R.A.R., D.W.B., J.W.C., M.A.M., N.A.C., R.D.M., K.C.C., N.P.Y., K.J.R.) and Tailoring Therapeutics (L.A.A.), Lilly Research Laboratories, Indianapolis, Indiana zhou_xin@lilly.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Drug Disposition (X.Z., L.R.A.R., D.W.B., J.W.C., M.A.M., N.A.C., R.D.M., K.C.C., N.P.Y., K.J.R.) and Tailoring Therapeutics (L.A.A.), Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Luc R A
authors.initials: LR
authors.lastname: Rougée
authors.affiliation: Drug Disposition (X.Z., L.R.A.R., D.W.B., J.W.C., M.A.M., N.A.C., R.D.M., K.C.C., N.P.Y., K.J.R.) and Tailoring Therapeutics (L.A.A.), Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: David W
authors.initials: DW
authors.lastname: Bedwell
authors.affiliation: Drug Disposition (X.Z., L.R.A.R., D.W.B., J.W.C., M.A.M., N.A.C., R.D.M., K.C.C., N.P.Y., K.J.R.) and Tailoring Therapeutics (L.A.A.), Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Cramer
authors.affiliation: Drug Disposition (X.Z., L.R.A.R., D.W.B., J.W.C., M.A.M., N.A.C., R.D.M., K.C.C., N.P.Y., K.J.R.) and Tailoring Therapeutics (L.A.A.), Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mohutsky
authors.affiliation: Drug Disposition (X.Z., L.R.A.R., D.W.B., J.W.C., M.A.M., N.A.C., R.D.M., K.C.C., N.P.Y., K.J.R.) and Tailoring Therapeutics (L.A.A.), Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Calvert
authors.affiliation: Drug Disposition (X.Z., L.R.A.R., D.W.B., J.W.C., M.A.M., N.A.C., R.D.M., K.C.C., N.P.Y., K.J.R.) and Tailoring Therapeutics (L.A.A.), Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Moulton
authors.affiliation: Drug Disposition (X.Z., L.R.A.R., D.W.B., J.W.C., M.A.M., N.A.C., R.D.M., K.C.C., N.P.Y., K.J.R.) and Tailoring Therapeutics (L.A.A.), Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Cassidy
authors.affiliation: Drug Disposition (X.Z., L.R.A.R., D.W.B., J.W.C., M.A.M., N.A.C., R.D.M., K.C.C., N.P.Y., K.J.R.) and Tailoring Therapeutics (L.A.A.), Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Yumibe
authors.affiliation: Drug Disposition (X.Z., L.R.A.R., D.W.B., J.W.C., M.A.M., N.A.C., R.D.M., K.C.C., N.P.Y., K.J.R.) and Tailoring Therapeutics (L.A.A.), Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Adams
authors.affiliation: Drug Disposition (X.Z., L.R.A.R., D.W.B., J.W.C., M.A.M., N.A.C., R.D.M., K.C.C., N.P.Y., K.J.R.) and Tailoring Therapeutics (L.A.A.), Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Ruterbories
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D001711:Biotransformation; D000068896:Canagliflozin / Q000493:pharmacokinetics; D002839:Chromans / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D005905:Glyburide / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D000077154:Rosiglitazone; D013045:Species Specificity; D013379:Substrate Specificity; D015238:Sulfotransferases / Q000378:metabolism; D045162:Thiazolidinediones / Q000493:pharmacokinetics; D000077288:Troglitazone
chemical_list: D002839:Chromans; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; C400322:cytochrome P-450 CYP2C subfamily; D000077154:Rosiglitazone; D000068896:Canagliflozin; D003577:Cytochrome P-450 Enzyme System; D008687:Metformin; D051544:Cytochrome P-450 CYP3A; D014453:Glucuronosyltransferase; D015238:Sulfotransferases; D000077288:Troglitazone; D005905:Glyburide