Comparative flubendazole and albendazole capacity to accumulate into hydatid cysts: drug efficacy assessment.

CEBALLOS, L; ALVAREZ, L; SANCHEZ BRUNI, S; ELISSONDO, C; DENEGRI, G; LANUSSE, C.

Leipzig, Alemania

Congreso; 11th International Congress of the European Association for Veterinary Pharmacology and Toxicology; 2009

European Association for Veterinary Pharmacology and Toxicology

Introduction: Cystic echinococcosis (CE) caused by the larval stage of Echinococcus granulosus is an important public health problem worldwide. Albendazole (ABZ) is the accepted drug for CE treatment, where a highly variable clinical success has been observed.  Low in vivo efficacy against CE has been reported for flubendazole (FLBZ) (1). However, FLBZ demonstrated activity against E. granulosus protoscoleces in vitro (2) and hydatid cysts developed in mice in vivo (3). The goals of the current work were: a) to evaluate the comparative ability of FLBZ and ABZ to diffuse into hydatid cysts under ex vivo conditions; b) to compare the plasma disposition and cysts distribution kinetics for both drugs in mice; and c) to compare the efficacy of FLBZ and ABZ against CE in mice. Materials and Methods:  Ex vivo diffusion study: Hydatid cysts recovered from eight-months infected mice were incubated (37 ºC, KRT buffer) with FLBZ, ABZ or albendazole sulphoxide (ABZSO) (5 nmol/ml, n= 4) between 5 to 45 min. After that, the cysts were analyzed by HPLC. In vivo pharmacokinetic (PK) study: BalbC mice (n= 88) were infected by i.p. inoculation of 1500 protoscoleces/animal. Eight months after infection the animals were allocated in two different groups and orally treated with either a FLBZ or ABZ cyclodextrin-based solution (5 mg/kg). Plasma and cysts samples were taken between 5 min and 12 h post-treatment (n= 4) and analyzed by HPLC for drug/metabolites quantification. Efficacy study: BalbC mice (n= 88) with nine months of cyst development were divided into three groups: I- Control (orally treated with water as a placebo); II- FLBZ: (orally treated with the same FLBZ-cyclodextrin solution used in the PK study);    III-ABZ: (orally treated with the same ABZ-cyclodextrin solution used in the PK study). All treatments (5 mg/kg) were performed twice a day during 15 days. After treatment, all animals were killed and the weight of the cysts collected from each animal was recorded. PK parameters and cyst weight differences between groups were analyzed by Student´s t-test and ANOVA, respectively. Results: After ex vivo incubation FLBZ cyst accumulation measured as AUC (39.3 ± 4.3 µg.min/ml) was higher (P< 0.05) than those observed for ABZ (24.4 ± 1.2 µg.min/ml) and ABZSO (12.9 ± 1.2 µg.min/ml). FLBZ was detected in plasma (AUC= 1.8 ± 0.2 μg.h/ml) and cysts (AUC= 0.3 ± 0.1 μg.h/ml) collected from treated-infected animals. Conversely, ABZ parent drug was not recovered neither in plasma nor in the cysts, being ABZSO the main molecule measured in plasma (AUC= 4.4 ± 0.4 μg.h/ml) and cysts (AUC= 1.5 ± 0.1 μg.h/ml). FLBZ induced a 90% reduction on cyst weight in comparison to those collected from untreated control mice (P< 0.05). However, no differences on cysts weight were observed between the ABZ treated (4.8 ± 5.3 g) and untreated control group (6.4 ± 4.3 g). Discussion and Conclusion: The excellent efficacy observed for FLBZ compared to ABZ (murine model) may be related to its ability to accumulate into the cyst. In contrast, after ABZ administration, the effect against hydatid cyst depends on ABZSO, a metabolite with lower anthelmintic potency compared to the parent compounds (FLBZ or ABZ).