Evaluation of drug-drug interaction on concomitant administration of anti-diabetics and hypolipidemics in in vivo models
Abstract
Diabetes mellitus is a multifactorial pathological condition, often associated with co-morbid condition of hyperlipidemia. Anti-diabetics and hypolipidemics are thus co-prescribed. Now, this use of multiple drugs or polypharmacy, however, increases the propensity of drug-drug interactions and adverse drug reactions. Present study was aimed to evaluate the effect of concomitant therapy of anti-diabetics and hypolipidemics on animal models induced with comorbid conditions of diabetes and hyperlipidemia. Diabetes was induced by Streptozotocin and Nicotinamide and hyperlipidemia was induced by High Fat Diet. Comorbid condition of both diabetes and hyperlipidemia was developed in rats. The rats were treated with antidiabetic drug Metformin and hypolipidemic drug Atorvastatin for 28 days. The safety and efficacy of concomitant therapy was evaluated by different biomarkers in serum and antioxidant levels in hepatic and renal tissues, collected from the rats. It was observed that concomitant therapy of Metformin and Atorvastatin was able to restore the blood glucose and triglyceride level by 69.93% and 54.61%, respectively. Concomitant therapy, however, was accompanied by increased oxidative stress in tissues, characterized by altered antioxidant levels. The hepatic and renal glutathione was diminished by 67.6% and 79.7% respectively, whereas, malondialdehyde level was enhanced by 31.7% and 83.3%, indicating oxidative stress induced tissue damage. This preliminary study was an attempt to mimic the comorbid diseased condition in animal model and to evaluate the safety and efficacy of concomitant therapy in animals that can be translated in human system to optimize therapeutic regimen.
Introduction
Diabetes Mellitus (DM) is a disease of improper metabolism of carbohydrates, proteins, lipids, due to lack of insulin hormone or insensitivity of cells to insulin, causing increased blood sugar level. (RahimiMadiseh et al., 2017) Insulin regulates the metabolism of carbohydrates, protein and fats. Insulin inhibits the release of free fatty acid (FFA) from the fat cells. Thus, insulin insufficiency results in increased FFA level, which in presence of glycogen in liver, stimulates the production of triglycerides in liver. Triglycerides in turn stimulates the production of VLDL cholesterol, thereby resulting in abnormal lipid profile or dyslipidemia. (Mooradian, 2009; Schofield et al., 2016) Therefore, dyslipidemia or abnormal lipid profile in blood, is a common comorbid condition in diabetic patients. (Indu et al., 2017; Joshi and Parikh, 2007) Abnormal lipid profile were reported among 67.1% of the diabetic patients of age 40 to 75 years in China. (Yan et al., 2016) Diabetes and dyslipidemia are the predisposing factors for the development of atherosclerosis, myocardial infarction, congestive heart failure, etc. (Joshi et al., 2014; Schofield et al., 2016) Thus diabetic patients are often co-prescribed with hypolipidemics, mainly statins. (Indu et al., 2017) A multi-centric study in 178 centres across India showed among 5400 diabetic patients screened, 75.25% were prescribed with statins. (Mithal et al., 2014) Meta-analysis data revealed use of statins results in one fifth reduction of cardiovascular events in patients. (Baigent et al., 2005) Thus diabetic patients are often prescribed with multiple medications. Polypharmacy or concomitant use of multiple medications not only increases the pill burden but also enhances the risk of drug-drug interactions and adverse drug reactions. (Payne and Avery, 2011) In vitro studies have been reported on interaction of antidiabetic drug Glimepiride with Atorvastatin and Rosuvastatin. (Galani and Vyas, 2010) Previous works have shown interaction of Metformin and Atorvastatin in vitro system. (Indu et al., 2018) However, an interactions of these two drugs in in vivo system is yet to be explored. Thus present study tried to evaluate the safety and efficacy of these two drugs in animal models. Comorbid condition of both diabetes and hyperlipidemia was developed in animals. Rats were then treated with concomitant medications of both Metformin and Atorvastatin. The present study thus, aimed to estimate the effect of concomitant medications in comorbid condition in animal models.
Source : Evaluation of drug-drug interaction on concomitant administration of anti-diabetics and hypolipidemics in in vivo models