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 absorption but its elimination from the blood is rapid so that high doses are necessary to obtain to therapeutic effect. In this study, we propose a strategy to enhance the bioavailability of DFMO by using lipidomimetic derivatives. Three lipidomimetic DFMO derivatives called O-DFMO, S-DFMO and Chol-DFMO were designed to reach easily the plasma and to be cleaved preferentially by plasma esterases progressively liberating free DFMO. Chol-DFMO only could be cleaved partially whereas the other compounds appeared to be stable in reconstituted intestinal medium and mouse plasma. Nevertheless, the use of DFMO derivatives in T. b. brucei experimental chemotherapy appeared as an interesting approach. Thus, O-DFMO was trypanocidal in vitro whereas DFMO, the active principle, was only trypanostatic. Nevertheless, this compound did not release DFMO in mouse blood as expected and acted therefore not as a prodrug. Oral treatment using low doses of compound O-DFMO was able to cure 40% mice while the active principle (eflornithine) administered at 50 fold higher molarity failed to cure any mice. This indicates that compound 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 released small amounts of DFMO in mice, however, too slight to obtain a therapeutic effect.
Loiseau
P M
PM
Biologie et Contrôle des Organismes Parasites, Châtenay-Malabry, France. Philippe.Loiseau@cep.u-psud.fr
Czok
M
M
Chauffert
O
O
Bourass
J
J
Letourneux
Y
Y
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003470:Culture Media; D004195:Disease Models, Animal; D004355:Drug Stability; D000518:Eflornithine / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D004950:Esterases / Q000378:metabolism; D005260:Female; D007928:Lethal Dose 50; D017737:Macrophages, Peritoneal / Q000187:drug effects; D051379:Mice; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D014344:Trypanocidal Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy*
D003470:Culture Media; D011355:Prodrugs; D014344:Trypanocidal Agents; D004950:Esterases; D000518:Eflornithine