In Vivo and In Vitro Pharmacokinetic Studies of a Dual Topoisomerase I/II Inhibitor.

Due to high mortality rates, new and more effective drugs are urgently needed in cancer therapy. The novel dual topoisomerase inhibitor P8-D6, a dimethylaminoethyl-substituted pyridophenanthroline, showed in vitro impressive induction of apoptosis in tumors such as ovarian cancer or multiple myeloma compared to the current standard therapy. The purpose of this study was to investigate its in vitro and in vivo pharmacokinetics and to discover further potential drug candidates. Samples of plasma, various tissues, urine, feces, and cell culture supernatants were examined by HPLC. In addition, the efficacy of the metabolites against ovarian cancer was determined in vitro. Three phase I metabolites were identified in vitro and in vivo, and one phase II metabolite was identified in vivo. Among the metabolites, N-dealkylated P8-D6 (P8-D6 mono) achieved efficacy similar to that of P8-D6 in ovarian cancer. P8-D6 showed a relevant inhibitory effect on the efflux pumps P-GP (IC(50) = 20.63 μM) and BCRP (16.32 μM). The calculated oral bioavailability in Sprague-Dawley rats was 21.5%, while P8-D6 had a high plasma protein binding of 99% and an extensive tissue distribution with an apparent volume of distribution between 57.69 (i.v.) and 82.92 (p.o.) L/m(2). Both P8-D6 and its metabolites were detected in urine and feces. This study provides a basis for the clinical application of P8-D6 and has also identified P8-D6 mono as a very potent and metabolically stable drug candidate.