Effects of Metformin and Losartane on Hepatic Cytochromes CYP3A, CYP2C and CYP2E1 Functioning at Metabolic Syndrome in Rats

Background. The study of drugs' possible metabolic and biological interactions in preclinical models is a necessary condition for improving the development of most combinations of medicines. Objective. The aim of our present study was to study the joint effects of metformin and losartan on hepatic CYP3A, CYP2C and CYP2E1 mRNA expression, their marker enzymes, liver antioxidant system and lipid peroxidation of adult rats with metabolic syndrome. Methods. Wistar albino male rats were divided into 5 groups (8 animals in each group): 1 – Control (intact rats), 2 – MS (rats with MS), 3 – MS + metformin (rats with MS and metformin (266.0 mg/kg of body weight, per os, 60 days)), 4 – MS + losartan (rats with MS and losartan (4.43 mg/kg of body weight, per os, 60 days)), 5 – MS + metformin + losartan (rats with MS and metformin and losartan treatment). MS was induced by full replacement of drinking water with 20% fructose solution (200 g/l). Metformin and losartan doses were calculated based on the species sensitivity coefficient. After 60 days of MS modeling, investigation of rat liver CYP3A, CYP2C and CYP2Е1 mRNA expression, their marker enzymes activities, as well as lipid peroxidation parameters were carried out. Results. It was demonstrated that combined administration of metformin and losartan affects the levels of CYP2E1, CYP2C23 and CYP3A2 genes expression, diclofenac hydroxylase activity, reduced glutathione contents, and the activity of lipid peroxidation processes. Conclusions. Our experiments showed that the noted changes were not the simple summation of the effects of metformin and losartan administered separately, but in most cases were determined only by losartan. Obtained results indicate the need for caution in the simultaneous prescription of metformin with losartan.