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 derived from melphalan and having a lymphotropism to avoid the hepatic first pass effect and enhance bioavailability after oral administration. Melphalan was linked to a ligand leading to a prodrug called 1,3-dp-melphalan which has structural analogy to triglycerides. The Molinema dessetae/Proechimys oris model was used for antiparasitic evaluation. Melphalan was macrofilaricidal in vitro against Molinema dessetae at 1mM, 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 rats, the maximum concentration and the cumulated quantities of melphalan in lymph were about 45-fold higher than those observed with the free drug under the same conditions. Moreover, the plasma concentration of melphalan was 2-fold higher than those observed after the administration of the free drug. These results are in favor of lymphotropic targeting as a novel approach to develop new orally active macrofilaricides.
Loiseau
P M
PM
Université de Paris-Sud, Châtenay-Malabry, France.
Deverre
J R
JR
el Kihel
L
L
Gayral
P
P
Letourneux
Y
Y
D000818:Animals; D004355:Drug Stability; D005369:Filaricides / Q000494:pharmacology*; D005370:Filarioidea / Q000187:drug effects*; D008196:Lymph / Q000378:metabolism*; D008297:Male; D008558:Melphalan / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012377:Rodentia
D005369:Filaricides; D011355:Prodrugs; D008558:Melphalan