The influence of enaminones on the transport and oral bioavailability of P-glycoprotein substrate therapeutic agents

Abstract

Objective: The enaminones have shown high P-gp affinity and may act as P-gp modulators. This study investigated the potential inhibition of the enaminones on paclitaxel efflux in vitro compared to cyclosporin A, a known P-gp inhibitor, and the effectiveness of select enaminones on paclitaxel oral absorption in rats. Methods: Caco-2 transport of [ 14 C ]paclitaxel was evaluated in presence of various enaminones at 10 −5 M. Concentration–effect (10 −10 M to 10 −4 M) profiles for the enaminones, DM27 and/or DM40, with paclitaxel and cyclosporin A were determined. Male Sprague–Dawley (250–275 g) rats were orally administered either [ 14 C ]paclitaxel (30 μCi/kg) or [ 14 C ]paclitaxel/DM27 (7 mg/kg) and blood samples were collected. Paclitaxel brain concentrations were measured. Results: Papp (A–B) of [ 14 C ]paclitaxel, with DM27 and DM40 at 10 −5 M, was significantly ( P<0.05) higher versus control. DM27 produced a 360% and a 139% increase in Papp (A–B)Paclitaxel and Papp (A–B)Cyclosporin, respectively. DM40 displayed a 131% increase in Papp (A–B)Paclitaxel whereas cyclosporin A produced a 213% increase in Papp (A–B)Paclitaxel. Rats in the DM27 group displayed large Vd ss/ F values (23.35 liters/kg versus 14.62 liters/kg) and lower AUC (5.47 μg/ml min versus 8.74 μg/ml min) versus control. However, significantly higher levels (2.25-fold) of paclitaxel were observed in the brains of the DM27 group. Conclusion: This study presents the enaminones as promising P-gp inhibitors with comparable potency to other P-gp inhibitors. Furthermore, the enaminones may improve conventional therapy when used in combination with P-gp substrate drugs.