In vivo and in vitro metabolism of the new anticancer drug bisantrene.

The metabolism of bisantrene, a new anthracene anticancer agent active in the treatment of disseminated breast cancer, was studied in vitro using rat liver S9 preparations and in vivo in patients receiving the drug as treatment for their cancers. 14C-ring labeled bisantrene (248 mCi/40 mg) plus cold bisantrene were administered IV to cancer patients (260-340 mg/m2). Fractional urine samples were collected at various time intervals up to 120 h after drug administration and analyzed by HPLC. The percent of total 14C excreted as unchanged parent drug per ml urine ranged from 37 to 79% in the 0 to 24 h samples. The remainder of the radioactivity appeared chromatographically just prior to the bisantrene peak, indicating that compounds more polar than the parent were present as transformation products. Metabolism of bisantrene was also studied in vitro under oxic (O2) and hypoxic (N2) conditions, using commercially available Aroclor 1254 induced rat liver S9 preparations. Following N2 incubation at 37 degrees C for 1 h there was no evidence of metabolism, whereas there was more than 50% decrease in parent drug within 1 h following O2 incubation in the presence of NADPH generating system, suggesting that the metabolic process involves an oxidative reduction. HPLC chromatogram profiles of the mixtures exposed to the activated S9 system indicated that there were at least 3 polar metabolites. In vitro human tumor clonogenic assay showed that the biological activity of bisantrene decreased greater than 4-fold when the drug was incubated with S9 preparations in the presence of NADPH and O2, indicating that the transformation process leads to relatively inactive bisantrene metabolites.