Difference in the Pharmacokinetics and Hepatic Metabolism of Antidiabetic Drugs in Zucker Diabetic Fatty and Sprague-Dawley Rats
| Autor: | David W. Bedwell, Luc Rougée, Jeff W Cramer, Nathan A Calvert, Nathan Yumibe, Kenneth J. Ruterbories, Kenneth C. Cassidy, Richard Moulton, Michael A. Mohutsky, Lisa A. Adams, Xin Zhou |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty endocrine system diseases CYP3A Pharmaceutical Science Pharmacology 030226 pharmacology & pharmacy Substrate Specificity Rats Sprague-Dawley Rosiglitazone Glibenclamide Troglitazone 03 medical and health sciences 0302 clinical medicine Insulin resistance Cytochrome P-450 Enzyme System Species Specificity Pharmacokinetics Internal medicine Glyburide medicine Animals Cytochrome P-450 CYP3A Humans Hypoglycemic Agents Canagliflozin Chromans Glucuronosyltransferase Biotransformation business.industry nutritional and metabolic diseases medicine.disease Metformin Rats Zucker 030104 developmental biology Endocrinology Liver Hepatocytes Administration Intravenous Thiazolidinediones Sulfotransferases business Drug metabolism medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 44:1184-1192 |
| ISSN: | 1521-009X |
| DOI: | 10.1124/dmd.116.070623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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