Herb drug interaction of Tinospora cordifolia (Willd.) Miers extract and Glimepiride: In vivo and in silico studies

Abstract

Tinospora cordifolia (Willd.) Miers (TC), family Menispermaceae is a well-known traditional herb reported in traditional Indian literature for the treatment of various disorders such as diabetes and cardiovascular diseases. Berberine, the chief active constituent of TC is reported to possess anti-diabetic potential along with other isoquinoline alkaloids. TC and its active constituent berberine both have been reported to be potent CYP2C9 inhibitor, thereby raising herb drug interaction (HDI) potential on co-administration with drugs metabolized through the CYP pathway. The present study evaluated the pharmacokinetic HDI of TC hydroalcoholic extract with Glimepiride (GP) after oral co-administration in Wistar rats using in vivo pharmacokinetic and in silico studies. After oral co-administration of TC extract (100 mg/kg) with GP (20 mg/kg) in rats, drug concentrations in plasma were determined using HPLC method. The main pharmacokinetic parameters of Cmax, Tmax, AUC, Vd, CL, and MRT0-t were calculated using Win Nonlin software. Also in silico molecular docking study using CYP2C9 (PDB ID: 1R90) as target protein and phytoconstituents (isoquinoline alkaloids) of TC as ligands were carried out using Auto Dock Vina 1.1.2 to determine their CYP2C9 interaction potential. The PK interactions studies demonstrated an increase in the systemic levels of GP. A significant increase in Cmax, AUC0-t and MRT0-t of GP (p<0.01) was observed, along with a substantial decrease in Vd and CL. In silico molecular docking studies on CYP2C9 demonstrated high inhibition potential of berberine (binding affinity: -9.6 kcal/mol) with formation of two hydrogen bonds with Ser 209 and Asn 474 in the active site of enzyme, complementing the literature reports as well as our in vivo PK findings. The results obtained from in vivo and in silico studies proposed that, for a co-administration of GP and TC extract, there exists a potentially significant PK HDI. This knowledge concerning potential HDI of GP might prove helpful for healthcare professionals as well as diabetic patients on GP therapy. It eventually warrants further studies to predict the pharmacokinetics and pharmacodynamics of GP in humans in case of HDI.