A pharmacology-based comparison of the activity of albendazole and flubendazole against Echinococcus granulosus metacestode in sheep

CEBALLOS, L; VIRKEL, G; ELISSONDO, C; CANTON, C; CANEVARI, J; MURNO, G; DENEGRI, G; LANUSSE, C; ALVAREZ, L

ACTA TROPICA

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2013

0001-706X

Cyst echinococcosis (CE) is a zoonotic disease caused by the larval stage of the Echinococcus granulosus helminth parasite.  The work reported here aimed to compare the efficacy of albendazole (ABZ) and flubendazole (FLBZ) against CE in naturally infected sheep. Additionally, their comparative pharmacokinetic behavior and the assessment of serum liver enzymes activities were studied.  Twelve (12) naturally infected sheep were allocated to the following experimental groups: Unmedicated control group, FLBZ-treated and ABZ-treated. Treatments were orally performed every 48 h, during 55 days at a dose rate of 10  and 8.5 mg/kg for FLBZ and ABZ respectively, (0.0032 mmoles/kg for both compounds).  The efficacy of the drug treatments was based-on protoscoleces?s vitality/viability. The kinetic disposition trial included an initial and a final pharmacokinetic study, which implicate the collection of blood samples after both, the first and the last drug administration. Blood samples were processed to measure drug concentrations by HPLC. The protoscoleces´ vitality observed in the untreated control group (98%) was significantly reduced in the presence of both ABZ (2%) and FLBZ (18%). A protoescoleces viability of 90, 25 and 33% were observed in the untreated control, FLBZ and ABZ treated groups, respectively. Ninety % of mice inoculated with protoescoleces belonging to Control group developed hydatid cysts in their peritoneal cavity, while only 25 (FLBZ) and 33% (ABZ) of mice inoculated with protoescoleces recovered from treated sheep, presented hydatid cyst in theirs abdominal cavity. Reduced FLBZ (R-FLBZ) was the main metabolite recovered in the bloodstream after oral administration of FLBZ to sheep. Low plasma concentrations of FLBZ parent drug were measured up to 48 h post-administration. ABZ was not detected in plasma at any time post-treatment, being its metabolites ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO2) recovered in plasma. Hepatotoxicity due to the continued treatment with either ABZ or FLBZ was not observed. A 3-fold increase ethoxyresorufin O-deethylase activity, a cytochrome P450 1A (CYP1A)-dependent enzyme reaction, was observed in liver microsomes obtained from sheep receiving ABZ, compared to those of the unmedicated and FLBZ-treated animals. In conclusion, FLBZ is an available anthelmintic which may be developed into an effective and safe drug for the human CE treatment. Despite the low plasma concentrations measured by FLBZ/R-FLBZ, an important reduction in PSC vitality was observed in cysts located in sheep liver. Modern pharmaceutical technology may help to greatly improve FLBZ systemic exposure improving its efficacy against CE.