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.

Tissue Specific Modulation of cyp2c and cyp3a mRNA Levels and Activities by Diet-Induced Obesity in Mice: The Impact of Type 2 Diabetes on Drug Metabolizing Enzymes in Liver and Extra-Hepatic Tissues

“…Our results on RNA transcripts are also consistent with phenotypic findings showing that cyp3a activity determined via hydroxylation of midazolam was significantly reduced in the two HFD groups compared to control group. In agreement with our finding, CYP3A activity has been reported to be also decreased in Zucker diabetic fatty (ZDF) rats using midazolam and testosterone as probes [ 40 ].…”

“…Obesity and diabetes have been shown to alter the expression and activity of hepatic CYP450s [ 14 , 28 , 29 , 35 , 36 , 37 , 38 , 40 , 41 , 42 , 55 , 56 , 57 ]. Clinical studies and animal experiments report mostly on hepatic CYP3A since it is the most important isoenzyme involved in the metabolism of prescribed drugs [ 58 , 59 ].…”

“…For instance, Woolsey et al have reported that CYP3A activity and CYP3A4 mRNA expression were reduced in humans and mice with nonalcoholic fatty liver disease [ 35 ]. However, results from animal studies are inconsistent from one study to the other [ 30 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. These discrepancies could be explained by the type of diabetes being studied (i.e., T1D vs. T2D), and the strategy used to induce diabetes (i.e., genetically-modified animals vs. chemicals vs. diet).…”

Increased susceptibility to troglitazone-induced mitochondrial permeability transition in type 2 diabetes mellitus model rat

“…In the drug development process, healthy animal models are employed in single-or repeated-administration toxicity studies. However, the expression level of drug metabolic enzymes and/or drug transporters could be altered by disease (Zhou et al, 2016), meaning that the biological/toxicological responses to drugs are likely to be more complicated than those observed under normal conditions. Thus, to precisely predict drug-induced toxicity, it may be necessary for some host factors, such as patient-specific molecular phenotypes, to be incorporated into in vitro and in vivo assay systems (Bell et al, 2016;Davidson et al, 2016).…”

Influence of the pharmacokinetic profile on the plasma glucose lowering effect of the PPARγ agonist pioglitazone in Wistar fatty rats

“…In humans, pioglitazone has a potency for cytochrome P450 3A4 (CYP3A) induction in vitro (Ripp et al, ; Sahi et al, ). The hyperglycemic condition has been shown to lead to lower plasma clearance of various drugs metabolised by CYPs in rats (Zhou et al, ). Therefore, the improvement of the hyperglycemic condition is also another possibility.…”