STUDIES ON LIPIDOMIMETIC DERIVATIVES OF ALPHA-DIFLUOROMETHYLORNITHINE(DFMO) TO ENHANCE THE BIOAVAILABILITY IN A TRYPANOSOMA B-BRUCEI MURINE TRYPANOSOMIASIS MODEL

DFMO, a trypanostatic drug, presents a satisfactory intestinal absorpt ion but its elimination from the blood is rapid so that high doses ore necessary to obtain a therapeutic effect. In this study, we propose a strategy to enhance the bioavailability oi DFMO by using lipidomimeti c derivatives. Three lipidomimetic DFMO derivatives celled O-DFMO, S-D FMO and Chol-DFMO were designed to reach easily the plasma and to be c leaved preferentially by plasma esterases progressively liberating fre e DFMO. Chol-DFMO only could be cleaved partially whereas the other co mpounds appeared to be stable in a reconstituted intestinal medium and mouse plasma. Nevertheless, the use of DFMO derivatives in T. b. bruc ei experimental chemotherapy appeared as on interesting approach. Thus , O-DFMO was trypanocidal in vitro whereas DFMO, the active principle, was only trypanostatic. Nevertheless, this compound did not release D FMO in mouse brood as expected and acted therefore not as a prodrug. O ral treatment using low doses of compound O-DFMO was able to cure 40 % mice while the active principle (eflornithine) administered at 50 fol d higher molarity failed to cure any mice. This indicates that compoun d O-DFMO acts by a specific mechanism which remains to be investigated . S-DFMO was less active and Chol-DFMO had no in vitro activity but re leased smell amounts of DFMO in mice, however, too slight to obtain a therapeutic effect.