METHIMAZOLE-MEDIATED ENHANCEMENT OF ALBENDAZOLE ORAL BIOAVAILABILITY AND ANTHELMINTIC EFFECTS AGAINST PARENTERAL STAGES OF TRICHINELLA-SPIRALIS IN MICE - THE INFLUENCE OF THE DOSE-REGIME

The influence of methimazole(R) (MTZ) inhibitor of the microsomal oxid ases on the systemic availability of the albendazole sulpho-metabolite s (ABZS-MT) albendazole-sulphoxide (ABZSO) and albendazole-sulphone (A BZSO(2)) land on its anthelmintic effects was investigated in a mouse model for helminthic infections. Plasma concentrations of the ABZS-MT were measured by high performance liquid chromatography (HPLC) followi ng treatment of Swiss CD-1 mice with albendazole (ABZ) alone or ABZ pl us MTZ, at both single and repeated doses. The anthelmintic effects we re assessed in age-matched mice similarly treated following infection with Trichinella spiralis. MTZ significantly (p < 0.01) increased the ABZS-MT plasma concentrations although the pharmacokinetic profile var ied greatly according to the dose of ABZ administered, When ABZ was gi ven at a single dose of 50 mg/kg followed by MTZ at 3 mg/kg, a cumulat ive effect was observed in the ABZS-MT plasma levels with pharmacokine tic parameters (T-max = 24 h, C-max = 30.88 mu g/ml and AUC = 1120.80 mu g h/ml) significantly (p < 0.01) higher than those following admini stration of ABZ alone (T-max = 3 h, C-max = 11.00 mu g/ml and AUC = 26 8.03 mu g h/ml), This cumulative effect was absent following administr ation of ABZ at 100 mg/kg where, after reaching a maximum (C-max = 27. 23 mu g/ml) at 3 h post-administration (T-max), the ABZS-MT plasma lev els felt down quickly to values under those obtained after administrat ion of ABZ at the same dose, but alone (AUC = 362.15 mu g h/ml vs. 340 .15 mu g h/ml, respectively). When ABZ was given at 50 mg/kg together with MTZ three times every 24 h, a rapid decrease was observed in the ABZS-MT plasma levels following administration of both the second and third doses, respectively. The pharmacokinetic profile of ABZS-MT foll owing administration of each of the three doses of ABZ at 100 mg/kg pl us MTZ was the same as that obtained after the single treatment. The r apid decrease bf the ABZS-MT plasma levels observed after the sustaine d treatment or after the single treatment at 100 mg/kg could be due to a microsomal oxidase inductive effect (probably the cytochrome P-450) caused by ABZSO. The co-administration of MTZ significantly (p < 0.01 ) increased the anthelmintic effects of ABZ against both migrating and encysted larvae of T. spiralis. Repeated treatment did not improve th e anthelmintic effects of the single treatment as the efficacies again st both stages of the parasite were always lower or identical to those of the single treatment at the corresponding doses. (C) 1998 Elsevier Science B.V.