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

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International Journal of Pharmaceutics


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 10-5M. Concentration-effect (10-10M to 10-4M) profiles for the enaminones, DM27 and/or DM40, with paclitaxel and cyclosporin A were determined. Male Sprague-Dawley (250-275g) rats were orally administered either [ 14C]paclitaxel (30μCi/kg) or [14C]paclitaxel/DM27 (7mg/kg) and blood samples were collected. Paclitaxel brain concentrations were measured. Results: Papp(A-B) of [14C]paclitaxel, with DM27 and DM40 at 10-5M, 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 (5.47μg/mlmin versus 8.74μg/mlmin) 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. © 2004 Elsevier B.V. All rights reserved.

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