Charakterisierung, Metabolismus und Interaktionspotential zytostatisch wirksamer 6-Aminobenzo[c]phenanthridine

Zebothsen, Inga

Besides assays for the evaluation of efficacy new drug candidates have to undergo extensive testings for enhancement of pharmaceutical drug safety and optimization of application. The objective of the present work was to contribute to the preclinical development of cytostatically active 6-aminobenzo[c]phenanthridines through studies on the physico-chemical characterization, the metabolism and the drug-drug interaction potential. In the context of the physico-chemical characterization solubility in aqueous media, lipophilicity, and pKa values were determined. According to the “rule of five” the results showed favourable characteristics indicating a good oral availability. Nevertheless an improvement of aqueos solubility is desirable for later application as well as for further testings. The examined compounds were transformed into a variety of metabolites by human and porcine liver microsomes as well as by human recombinant CYP450-isoenzymes. Metabolites were identified by LC-MS. Several isoenzymes were involved in the metabolism, with CYP3A4 playing a major role. Studies on the drug-drug interaction potential of selected derivatives showed a high risk for BP-11 for interactions with the cytochrom P450- isoenzymes CYP1A2, CYP2C9, CYP2D6 and CYP3A4. BP-D7, with the highest efficacy in in vitro and in vivo assays showed only a slightly increased probability for interactions with drugs, also metabolized by CYP3A4.



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Zebothsen, Inga: Charakterisierung, Metabolismus und Interaktionspotential zytostatisch wirksamer 6-Aminobenzo[c]phenanthridine. 2005.


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