Evaluation of albendazole prodrugs in experimental trichinellosis.
BACKGROUND
Two albendazole (ABZ) prodrugs, N-methoxycarbonyl-N'-[(2-nitro-4-propylthio) phenyl] thiourea (compound 2), and N-methoxycarbonyl-N'-[(2-nitro-5-propylthio) phenyl] thiourea (compound 3) have recently been synthesized. These compounds showed greater solubility than ABZ itself.


METHODS
In order to evaluate the biotransformation of compounds 2 and 3 to ABZ and/or ABZ-sulphoxide (ABZ-SO), plasma samples taken from mice treated with the prodrugs were analyzed by HPLC. Also, the anthelmintic activity of compounds 2 and 3 against Trichinella spiralis was evaluated in the mice experimentally infected with the parasite.


RESULTS
The presence of ABZ and/or ABZ-SO was demonstrated in plasma samples taken at different time intervals after prodrug administration, although their levels were low compared to those reached in mice treated with ABZ. Additionally, prodrugs 2 and 3 were also detected in these samples. In regard to the anthelmintic activity of ABZ prodrugs, it was shown that compound 3 was more active than compound 2. Additionally, it was as effective as ABZ against T. spiralis pre-adult, adult, and female fecundity. However, compound 3 was not as active as ABZ against the muscle stage of the parasite.


CONCLUSIONS
Compound 3 had better anthelmintic activity against T. spiralis than compound 2. The bioconversion of compounds 2 and 3 to ABZ and/or ABZ-SO was demonstrated by HPLC, but they did not reach equivalent concentrations to that of ABZ. Prodrugs 2 and 3 were also present in plasma samples, suggesting that prodrugs were not efficiently reduced in the intestine of mice.
Yépez-Mulia
L
L
Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Hospital de Pediatría, Instituto Mexicano del Seguro Social, México, D.F., Mexico. lilianyepez@yahoo.com
Morales-Hurtado
R
R
Viveros-Guzmán
N
N
Cedillo-Rivera
R
R
Hernández-Luis
F
F
Castillo
R
R
Hernández-Campos
A
A
Muñoz
O
O
D015766:Albendazole / Q000627:therapeutic use*; D000818:Animals; D000871:Anthelmintics / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017207:Rats, Sprague-Dawley; D014235:Trichinellosis / Q000188:drug therapy*
D000871:Anthelmintics; D015766:Albendazole