ALBENDAZOLE FAILURE TO CONTROL RESISTANT NEMATODES IN LAMBS: LACK OF EFFECT OF FASTING-INDUCED IMPROVEMENT ON DRUG ABSORPTION

ALVAREZ, L; ENTROCASSO, C; LIFSCHITZ, A; MANAZZA, J; CEBALLOS L; BORDA, B; LANUSSE, C

JOURNAL OF PARASITOLOGY

AMER SOC PARASITOLOGISTS

Año: 2010

0022-3395

ABSTRACT:  The time and level of parasite exposure to active drug concentrations determine the efficacy for the most of the anthelmintic drugs used in ruminants. Enhanced plasma availability of albendazole sulphoxide (ABZSO), the active metabolite of albendazole (ABZ), has been described in feed restricted sheep. The aim of the current work was to determine if the absorption-related pharmacokinetic changes derived from fasting animals prior to drug treatment, modify the clinical efficacy of ABZ against resistant gastrointestinal (GI) nematodes in lambs. Forty Corriedale lambs, naturally infected with resistant GI nematodes were divided into 4 groups. Controls were fed ad libitum and did not receive any drug treatment. Treated animals were fed ad libitum up to 30 min prior to treatment with ABZ (3.8 mg/kg) by the intraruminal (i.r.) route. Control fasted animals were not fed during the 24 hr period prior to the start of the experiment and did not receive any drug treatment. A second treated group of animals were fasted 24 hr prior to the treatment with ABZ, as previously described for the fed-treated group. Blood samples were collected over 72 hr post-treatment from 6 animals in each treated group. Plasma samples were analyzed by HPLC after clean up and solid phase extraction. The estimated pharmacokinetic parameters were statistically compared using parametric statistical tests. The indirect estimation of the efficacy of the different treatments was performed by the fecal egg count reduction test (FECRT). Additionally, 4 animals randomly chosen from the control-fed and treated groups were killed 13 days post-treatment to evaluate the efficacy against different adult nematode parasites. The results were statistically compared by parametric and non-parametric tests.  Significantly (P<0.05) higher peak plasma concentration and AUC values were observed for both the ABZSO and ABZ-sulphone (ABZSO2) metabolites, in fasted compared to fed animals. These kinetic results may be due to a fasting-induced delay in the GI transit time, which  increases ABZ dissolution and GI absorption. However, a poor ABZ efficacy (measured as FECRT) compatible with a high degree of nematode resistance was obtained in both fed (48%) and fasted (49%) animals. Haemonchus contortus and Trichostrongylus colubriformis appeared as the more reluctant species with respect to ABZ treatment. The efficacy against H. contortus ranged between 37 (fed) and 54% (fasted), while activity against T. colubriformis was 0 (fed) and 16% (fasted).  Under these experimental conditions, the fasting-induced improvement on ABZ systemic availability (> 60%) did not improve its activity against nematodes with a high degree of resistance. However, the data described here for a highly resistant nematode population should not discourage the use of fasting as a practical and well proven management tool for parasite control in ruminants.