An in-vivo herb-drug interaction study of IME-9 and glimepiride in nicotinamide-STZ-induced diabetic rats

• Glimepiride is primarily metabolized by the CYP2C9 enzyme. • IME-9 is a mixture of herbs, has the potential to inhibit the CYP2C9 enzyme. • The effect of the co-administration of Glimepiride and IME-9 in diabetes induced (Nicotinamide-STZ) rats for 21 days was studied. • Changes in pharmacodynamic parameters were noted, but no significant changes in pharmacokinetic parameters of Glimepiride were observed. Currently, herbs are frequently employed for medicinal or dietary purposes alongside both prescribed and over-the-counter medications. Despite being perceived as natural and benign, herbs carry the potential to interact with medications, potentially leading to adverse reactions or diminished efficacy of the medications. It is worth noting that herbs comprise different amounts of active phytochemicals that can affect enzymatic systems, transporters and physiological processes. The focus of this study is to investigate the effects of the herbal formulation IME-9 on the pharmacokinetics (PK) and pharmacodynamics (PD) of Glimepiride (GP) and whether it is advantageous, detrimental or has no consequences. In this study, the PK and PD interactions of GP (0.82 mg/kg) with IME-9 (132.24 mg/kg p.o.) was studied in diabetic rats (induced by Nicotinamide-STZ) by concomitant administration of both the drugs orally for a period of 21 days. The RP-HPLC technique was devised and validated in accordance with the guidelines set by the US Food and Drug Administration (FDA). PK and PD parameters were computed on both day 1 and 21 in vivo. In silico molecular docking investigations were conducted using Autodock Vina 1.2.3 to assess the binding affinity of the 46 primary phytoconstituents present in IME 9 with CYP2C9 enzymes. Toxicity assessments were carried out utilizing the MTT assay. Concurrent administration of GP and IME-9 in diabetic rats resulted in elevated Cmax and AUC 0-48hr s of GP, while no alteration in Tmax was noticed. This led to a reduction in Vd and CL together with an increase in t 1/2 and mean residence time. Notably, the combination treatment (GP+IME-9) significantly decreased FBGL, TC and TG levels compared to individual therapy groups, suggesting synergistic pharmacodynamic effects. In silico molecular docking predictions revealed that the majority of phytoconstituents present in IME-9 formulation act as an inhibitor of the CYP2C9 enzyme. GP and IME-9 together could enhance the hypoglycemic effect and increase systemic exposure of GP.