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 [14C]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 [14C]paclitaxel (30 microCi/kg) or [14C]paclitaxel/DM27 (7 mg/kg) and blood samples were collected. Paclitaxel brain concentrations were measured. RESULTS: Papp(A-B) of [14C]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 Vdss/F values (23.35 liters/kg versus 14.62 liters/kg) and lower AUC (5.47 microg/ml min versus 8.74 microg/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.