Abstracts

Multidrug resistance (MDR), often conferred by the active extrusion of drugs from the cell, is a phenomenon often seen in cancer cells that may become resistant to a wide spectrum of drugs with varying chemical structures or cellular targets. Human P-glycoprotein (P-gp) encoded by MDR1 and the multidrug resistance-associated protein (MRP1) are both members of the superfamily of ATP binding cassette (ABC) transporter proteins. This MDR1 gene product P-gp has been found in tumor cells and due to its overexpression in these cells, allows for protection against several anticancer drugs. In addition to cancer chemotherapy, the presence of MDR has been noted in drug resist to other diseases, i.e. malaria, AIDS and epilepsy. Studies in our laboratories on this occurrence has been noted in the pharmacokinetic evaluation of several anticonvulsant enaminones which have shown high efflux ratios and are recognized by P-gp and/or the MRP. This study was designed to evaluate 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. Caco-2 transport of [14C]paclitaxel was evaluated in the presence of various enaminones at 10-5 M. Concentration-effect (10-10 to 10-4 M) profiles for the enaminones, 3-(4-chlorophenylamino)-5-methylcyclohex-2-enone (DM27) and/or methyl 4-(3-phenylpropylamino)-6-methyl-2-oxocyclohex-3-ene carboxylate (DM40), with paclitaxel and cyclosporin A were determined. Male Sprague-Dawley (250-275 g) rats were orally administered either [14C]paclitaxel (30 [mu]Ci/kg) or[14C]paclitaxel/DM (7 mg/kg) and blood samples were collected. Paclitaxel brain concentrations were measured. Papp(A-B) of [14C]paclitaxel, with DM27 and DM40 at 10-5 M, was significantly (P[lt]0.05) higher versus control. DM27 produced a 360% and 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 21% 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 [mu]g/mL min. versus 8.74 [mu]g/mL min.) versus control. However, significantly higher levels (2.25-fold) of paclitaxel were observed in the brains of the DM27 group. This study presents the enaminones as promising P-gp inhibitors with comparable potency to other P-gp inhibitors. Further, the enaminones may improve conventional therapy when used in combination with P-gp substrate drugs. (Supported by a grant from the National Institutes of Health (1R21 GM63494-01), (K.R.S.) and from the National Cancer Institute (CA87564-01A))