Effects of Diabetes Mellitus Induced by Alloxan on the Pharmacokinetics of Metformin in Rats: Restoration of Pharmacokinetic Parameters to the Control State by Insulin Treatment

Abstract

PURPOSE. To test the effect of insulin treatment on the pharmacokinetics of metformin in rats with diabetes mellitus induced by alloxan (DMIA rats). The following results were reported from other studies. Metformin was metabolized via hepatic CYP2C11, 2D1, and 3A1/2 in rats. In DMIA rats, the protein expression and mRNA levels of hepatic CYP2C11 and 3A1/2 decreased and increased, respectively. In rat model of diabetes mellitus induced by streptozotocin, the protein expression of hepatic CYP2D1 was not changed. The increase in hepatic CYP1A2, 2B1, and 2E1, and decrease in hepatic CYP2C11 in DMIA rats was returned to the controls by insulin treatment. METHODS. Metformin (100 mg/kg) was administered intravenously and orally to the control rats, DMIA rats, and DMIA rats with insulin treatment for 3 weeks (DMIA rats with insulin). RESULTS. After intravenous administration of metformin to the DMIA rats, the CL R and CL NR of the drug were significantly slower than the controls. After oral administration of metformin to the DMIA rats, the AUC of the drug was also significantly greater than the controls. After intravenous administration of metformin to the DMIA rats with insulin, the significantly slower CL NR of the drug in the DMIA rats was returned to the controls. The altered pharmacokinetic indices observed following intravenous and oral administration of metformin to DMIA rats returned to the control values in the DMIA rats with insulin. CONCLUSIONS. The significantly slower CL NR of metformin in the DMIA rats could be due to the decrease in hepatic CYP2C11 than the controls. The comparable CL NR of metformin between the DMIA rats with insulin and the control rats could be due to restoration of hepatic CYP enzyme changes in DMIA rats to the controls.

Next generation sequencing of sex-specific genes in the livers of obese ZSF1 rats

“…We found male-specific gene expression for Cyp2c11 in obese ZSF1 rats and in their lean controls, which is in accordance with literature [40]. In both animal models of type 1 diabetes, STZ-and alloxan-induced diabetes, Cyp2c11 expression was impaired in the liver [41]. In our type 2 diabetes rat model, no significant differences of hepatic Cyp2c11 expression was found between male obese (diabetic) and lean (non-diabetic) ZSF1 rats.…”

Assessment of Chemical Composition of Spirulina Platensis and its Effect on Fasting Blood Glucose and Lipid Profile in Diabetic Rats

“…Diabetic rats treated with Metformin showed improvement in body weight as compared with diabetic rats. This result was in line with that reported Lee et al, (2008) (25) , although it disagreed with Lee and Morley, (1998) (26) who stated that Metformin exhibited no change in the body weight with respect to control group. Spirulina increased body weight in diabetic rats, which may be explained by increased insulin secretion or increased food consumption, since it helps diabetic patients to maintain their body weight.…”

Influence of Plantago ovata husk (dietary fiber) on the bioavailability and other pharmacokinetic parameters of metformin in diabetic rabbits

“…Several authors indicate that the pharmacokinetics of metformin after oral administration is well described by a three-compartment open model [22, 29, 34] although most researchers have evaluated its pharmacokinetics using a non-compartment model [25, 27, 31–33, 36, 45, 46]. In this study, we tried a compartmental analysis of the results obtained, but the plasma concentration-time data were not adequately fitted to the classic open compartmental models tested, so finally, we applied a non-compartmental model.…”

“…Metformin pharmacokinetics has been fully documented in humans [20–28] but less in animal species such as rats [31–33], cats [34, 35] and horses [36]. …”