STUDY OF LYMPHOTROPIC TARGETING AND MACROFILARICIDAL ACTIVITY OF A MELPHALAN PRODRUG ON THE MOLINEMA-DESSETAE MODEL

This study deals with the design of a new macrofilaricidal drug derive d from melphalan and having a lymphotropism to avoid the hepatic first pass effect and enhance bioavailability after oral administration. Me lphalan was linked to a ligand leading to a prodrug called 1,3-dp-melp halan which has structural analogy to triglycerides. The Molinema dess etae/Proechimys oris model was used for antiparasitic evaluation. Melp halan was macrofilaricidal in vitro against Molinema dessetae at 1 mM, inactive in vivo after an oral single dose at 164 mumol/kg while the prodrug 1,3-dp-melphalan was active against adult worms after a single dose at 82 mumol/kg. After an oral administration of the prodrug to r ats, the maximum concentration and the cumulated quantities of melphal an in lymph were about 45-fold higher than those observed with the fre e drug under the same conditions. Moreover, the plasma concentration o f melphalan was 2-fold higher than those observed after the administra tion of the free drug. These results are in favor of lymphotropic targ eting as a novel approach to develop new orally active macrofilaricide s.