Multitarget Drug Discovery Approach for Diabetes mellitus and gastroenteropathy as its comorbidity Management with Metformin quercetin

Abstract

Abstract newlineDiabetes is a complex multifactorial disease. The prevalence of diabetes throughout the newlineworld is increasing, nearly half (46%, 415 million) of the adult population is living with newlinediabetes and majority of them are with Type 2 Diabetes Mellitus (T2DM). T2DM mediated newlinealterations in the pharmacokinetics-pharmacodynamics (PK-PD) of the drugs is responsible for newlinethe lack of rationalized therapeutic management of it. Because of which, the majority of the newlineT2DM cases progress to associated comorbidities depending on patient related factors To newlineaddress the same, we used systematic approach taking T2DM and T2DM associated newlinegastroenteropathic complications as a case example. Therefore, the primary objective was newlineexploring the T2DM mediated alterations in the PK of metformin. For the same, we developed a newlineclinically simulated animal model of T2DM and non-steroidal anti-inflammatory drugs newline(NSAID)-induced gastroenteropathy at different phases of T2DM. We found that, both newlinemetformin untreated and treated group showed significant morbidity/mortality after post newlineT2DM-120 days. Hence, three time-points were selected for PK (post T2DM-0th, 60th, 120th newlineday) studies. T2DM significantly exaggerated the gastroenteropathic complication which newlineincreases with respect to its progression. Even five days and three days treatment with newlinediclofenac at its therapeutic dose was sufficient to develop gastroenteropathy at initial and newlinechronic phase of diabetes respectively, when fasted on last study day. newlineT2DM significantly increases the AUC (area under curve) and Cmax (maximum plasma newlineconcentration), while decreases CL (clearance), and Vd (voulme of distribution) of the metformin newlinewith respect to its progression and/or presence of NSAID-gastroenteropathy. Post T2DM-60 newlinedays metformin (50 mg/kg; b.i.d.; P.O.) treatment were able to prevent significant rise in AUC0- newlineand#8734; and Cmax and decrease CL and Vd, unlike 0 and 120-day (with and without NSAIDgastroenteropathy). newlineThis increases the probability of metformin intolerance, associated sideeffects newlineand/or adverse effects. Therefore, based on our previous experiences and literature we newlineselected quercetin (QCT) as a potential lead with multi-targetability to manage this complex newlinemultifactorial disease. QCT (50 mg/kg; b.i.d.; P.O.) efficiently prevents T2DM progression to newlineNSAID-induced gastroenteropathy. Concomitant administration of metformin with QCT newlinesignificantly reduces fasting blood glucose in diabetic rats without inducing hypoglycemia in newlinenormal rat. Concomitant administration of METF with QCT significantly decreased all PK newlineparameters towards normal when compared with METF alone. QCT plus metformin caused newlinesignificant rise in CLint (heaptic intrinsic clearance) and Vmax (the velocity maximum) in T2DM and newlineT2DM with NSAID-gastroenteropathic rats compared to their respective controls. newlineIn conclusion the quercetin plus metformin administration in diabetic rats with newlinegastroenteropathic complications shows beneficial drug(s)-disease(s) interactions. The degree newlineof therapeutic rationalization may be increased with respect to different phases of T2DM and/or newlineassociated co-morbidity. newline