Evaluation of hepatic CYP2D1 activity and hepatic clearance in type I and type II diabetic rat models,before and after treatment with insulin and metformin

IntroductionConversion in the metabolism of drugs occurs in diabetes mellitus. Considering the importance of metabolic enzymes’ activities on the efficacy and safety of medicines, the changes in liver enzymatic activity of CYP2D1 and its related hepatic clearance, by using Dextromethorphan as probe in the animal model of type I and type II diabetes, before and after treatment, was assessed in this study.MethodsMale Wistar rats were randomly divided into 6 groups. Seven days after induction of diabetes type I and type II, treatment groups were received insulin and metformin daily for 14 days, respectively. In day 21, rats were subjected to liver perfusion by Krebs-Henseleit buffer containing Dextromethorphan as CYP2D1 probe. Perfusate samples were analyzed by HPLC fluorescence method in order to evaluate any changes in CYP2D1 activity.ResultsThe average metabolic ratio of dextromethorphan and hepatic clearance were changed from 0.012 ± 0.004 and 6.3 ± 0.1 in the control group to 0.006 ± 0.0008 and 5.2 ± 0.2 in the untreated type I diabetic group, and 0.008 ± 0.003 and 5.0 ± 0.6 in the untreated type II diabetic rats. Finally, the mean metabolic ratio and hepatic clearance were changed to 0.008 ± 0.001 and 5.4 ± 0.1, and 0.013 ± 0.003 and 6.1 ± 0.4 in the treated groups with insulin and metformin, respectively.ConclusionIn type I diabetic rats, corresponding treatment could slightly improve enzyme activity, whereas the hepatic clearance and enzyme activity reached to the normal level in type II group. Graphical abstractOpen in a separate window.