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 (MDR) in haematological malignancies because of their tolerance and their retained efficacy in serum. We have also shown that cinchonine was more efficient than quinine as an anti-MDR agent in vitro, ex vivo and in vivo after parenteral administration. Here, we report that cinchonine administered per os (po) is much more active than quinine po in circumventing MDR in rats bearing resistant colon tumours. The pharmacokinetics of cinchonine and quinine administered po in rat are shown to be very different. Cinchonine demonstrates a greater absolute bioavailability than quinine (44% versus 30%, respectively). Its serum concentration correlates with the anti-MDR activity measured ex vivo and in vivo. Cinchonine administered po does not significantly modify the pharmacokinetics of intravenous doxorubicin (DXR). However, cinchonine induces a significant increase of DXR uptake in organs which express the mdr1 gene (liver, kidney, lung). When associated with VAD (vincristine, adriamycin, dexamethasone) combined therapy in rats, cinchonine does not significantly increase the toxicity of the cytotoxic drugs. Based on these experimental data, a phase I clinical trial is currently in progress to test the tolerance of this potent MDR-reversing agent administered po.