Enhancement of Oral Bioavailability of Paclitaxel With The Help Of Natural Bioenhancer

Abstract

Paclitaxel is a substrate for ATP-binding cassette (ABC) transporters such as Pglycoprotein-mediated efflux, and its metabolism in humans is mainly catalyzed by CYP 3A4 and 2C8. Piperine, an isoflavonoid, is supposed to be an inhibitor of some ABC transporters, and its oxidative metabolism is catalyzed by CYP 3A4 and 2C8. The purpose of this study was to investigate the effect of orally administered piperine on the pharmacokinetic profile of paclitaxel administered orally in rabbits. Rabbits have been divided into 4 groups. The treatment protocol consists of single oral dose of paclitaxel (15mg/kg) (Group 1), single oral dose of piperine (7.5mg/kg, 15mg/kg and 30mg/kg) (Group 2, 3 and 4) followed by single oral dose of paclitaxel (15mg/kg). Blood samples were collected from marginal ear vein at 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6,8,10, 12 and 24 hours and plasma was separated for HPLC analysis. The plasma concentration-time data were analysed by non-compartmental pharmacokinetic analysis. The presence of 30mg/kg piperine (group 4) significantly (p < 0.05) increased the area under the plasma concentration–time curve (AUC0-t, 2.74 folds) of orally administered paclitaxel. Piperine also decreased significantly (p < 0.05) the total plasma clearance (CL/F) of all treated groups of paclitaxel when compared with control group. . Piperine also increased the peak concentration (Cmax) of paclitaxel significantly (p < 0.05 by 7.5 mg/kg, 1.494 folds; p < 0.05 by 15 mg/kg, 1.836 folds; p < 0.05 by 30mg/kg, 2.737 folds higher).Piperine also increased the mean residual time (MRT) of paclitaxel significantly (p < 0.05 by 7.5mg/kg, 15mg/kg and 30mg/kg, 1.123 folds; 1.125 folds and 1.330 folds higher respectively. Piperine also increased the elimination half life (t1/2) of paclitaxel significantly (p < 0.05 by 7.5mg/kg; 15mg/kg and 30mg/kg, 1.13; 1.33 and 1.433 folds higher respectively). Piperine also declined the elimination rate constant (β) of paclitaxel significantly (p < 0.05 by 7.5mg/kg; 15mg/kg and 30mg/kg, 1.15; 1.35 and 1.48 folds declined respectively). It can be concluded from the study that paclitaxel administered with piperine at different doses has been exhibited higher t1/2, AUC, Cmax, MRT values and lower clearance values and elimination rate constant(β). The increase in plasma concentration of paclitaxel in rabbits administered with piperine could be attributed to the ability of piperine to enhance the intestinal absorption, to inhibit the metabolism in liver and to inhibit P-glycoprotein mediated drug efflux during intestinal absorption. The

Department of Pharmaceutical Sciences and Technology, MRSPTU presence of piperine improved the systemic exposure of paclitaxel in this study. The pharmacokinetic interaction between them should be taken into consideration when paclitaxel is used with piperine or the dietary supplements full of piperine.