CINCHONINE PER-OS - EFFICIENT CIRCUMVENTION OF P-GLYCOPROTEIN-MEDIATED MULTIDRUG-RESISTANCE

We have previously suggested that quinine and cinchonine could be good candidates for the clinical circumvention of multidrug resistance (MD R) in haematological malignancies because of their tolerance and their retained efficacy in serum. We have also shown that cinchonine was mo re efficient than quinine as an anti-MDR agent in vitro, ex vivo and i n vivo after parenteral administration. Here, we report that cinchonin e administered per os (po) is much more active than quinine po in circ umventing MDR in rats bearing resistant colon tumours. The pharmacokin etics of cinchonine and quinine administered po in rat are shown to be very different. Cinchonine demonstrates a greater absolute bioavailab ility than quinine (44% versus 30%, respectively). Its serum concentra tion correlates with the anti-MDR activity measured ex vivo and in viv o. Cinchonine administered po does not significantly modify the pharma cokinetics of intravenous doxorubicin (DXR). However, cinchonine induc es a significant increase of DXR uptake in organs which express the md r1 gene (liver, kidney, lung). When associated with VAD (vincristine, adriamycin, dexamethasone) combined therapy in rats, cinchonine does n ot significantly increase the toxicity of the cytotoxic drugs, Based o n these experimental data, a phase I clinical trial is currently in pr ogress to test the tolerance of this potent MDR-reversing agent admini stered po.