The aim of this study is to characterize the intestinal transport of vincristine and to predict the human intestinal permeability and fraction absorbed using SPIP.Permeability Coefficient and the effect of P-gp modulators on Vincristine Sulphate were studied in anaesthetized rats. Single Pass Intestinal Perfusion was performed in the jejunal segment. The rationale for the selection of jejenum is due to the overexpression of P-glycoprotein when compared with other segments. Drug solution (150µg/ml) in phosphate buffer saline was perfused at a flow rate of 0.2ml/min.Besides,P-gp inhibitor verapamil(200 µg/ml) and inducer Rifampicin (60mg/ml) were coperfused with Vincristine to detect its disposition characteristics affected by P-gp .Drug concentrations in samples were analyzed using HPLC. Stability studies were conducted to ensure the loss of Vincristine due to absorption.The effective permeability value of Vincristine (150µg/ml) in the jejunal segment was found to be lower due to the efflux mediated by P-gp.When coperfused with verapamil its permeability significantly enhanced as it is a P-gp inhibitor and vice versa with Rifampicin which is a P-gp inducer. Subsequently the human intestinal permeability was estimated considering Peff(human) =1.04 Peff(rat)-0.0003. P-Glycoprotein mediated drug resistance is one of the serious limitations of Vincristine efficacy and jejunal segment is found to have major MDR expression. The Peff value of Vincristine was found to be increased upon the co-perfusion with verapamil and similarly reduced with Rifampicin which are inhibitors & inducers respectively indicating Vincristine is efficiently transported by P-gp. Hence, vincristine satisfies all the prerequisites to be a P-gp substrate.
Loading....