Multitarget Drug Discovery Approach for Diabetes Mellitus and Gastroenteropathy as its Comorbidity: Management with Metformin and Quercetin

Abstract

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