The comparative plasma disposition kinetics of albendazole (ABZ), fenbendazole (FBZ) and oxfendazole (OFZ) following their oral administration (5 mg/kg) to adult sheep was characterized. Jugular blood samples were taken serially over a 144 h period and plasma was analysed by high performance liquid chromatography (HPLC) for ABZ, ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO2) (ABZ treatment), and for FBZ, OFZ and FBZ sulphone (FBZSO2) (FBZ and OFZ treatments). While the ABZ parent drug was not detected at any time post-treatment, ABZSO and ABZSO2 were the analytes recovered in plasma after oral administration of ABZ to sheep. The active ABZSO metabolite was the main analyte recovered in plasma (between 0.25 and 60 h post-treatment), accounting for 71% of the total AUC. FBZ, OFZ and FBZSO2 were the analytes detected in plasma following the oral administration of both FBZ and OFZ to sheep. Low concentrations of FBZ were found in plasma between 4 (FBZ treatment) or 8 h (OFZ treatment) and 72 h post-treatment. The plasma profile of each analyte followed a similar pattern after both treatments; OFZ being the main component detected in plasma. The plasma disposition of ABZ metabolites was markedly different to that of FBZ derivatives. ABZSO exhibited faster absorption and a higher Cmax than OFZ (both treatments). Furthermore, while ABZSO declined relatively rapidly in plasma reaching non-detectable concentrations at 60 h post-ABZ administration, OFZ was found in plasma for up to 120 (FBZ treatment) and 144 h (OFZ treatment).(ABSTRACT TRUNCATED AT 250 WORDS)

1. The metabolism of albendazole (ABZ), albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2) by ruminal, abomasal and ileal fluids of sheep and cattle was investigated under anaerobic conditions in vitro. 2. None of the compounds was metabolically changed by incubation with abomasal fluids of sheep and cattle. 3. ABZ and ABZSO were extensively metabolized by sheep and cattle ruminal and ileal fluids. ABZSO2 was unaffected by incubation with these gastrointestinal fluids. 4. The rate of ABZ oxidation into ABZSO was greater for cattle ruminal and ileal fluids than for sheep fluids. 5. ABZSO was reduced back to ABZ by ruminal and ileal fluids of both species. This reducing activity was significantly higher for both ruminal and ileal fluids of sheep compared with those of cattle.

The gastrointestinal (GI) distribution and plasma disposition kinetics of albendazole (ABZ) metabolites after oral administration of netobimin (NTB) to cattle were studied. Eight Holstein steers (150-180 kg) were surgically fitted with permanent cannulae in the rumen, abomasum and ileum. After post-surgical recovery, the animals were treated orally with a suspension of netobimin zwitterion (400 mg/ml) at 20 mg/kg. Jugular blood and ruminal, abomasal and ileal fluid samples were taken serially over a 96 h period and analysed by HPLC for NTB and its metabolites, including ABZ, ABZ sulphoxide (ABZSO), ABZ sulphone (ABZSO2) and amino-albendazole sulphone (NH2ABZSO2). NTB parent drug was only found in the GI tract and for only 12-18 h post-treatment. ABZSO and ABZSO2 were the main metabolites found in plasma, being present for 30-36 h. These metabolites were exchanged between plasma and different GI fluids and were greatly concentrated in the abomasum. This phenomenon may account for the presence of ABZ, ABZSO and ABZSO2 in the GI tract for 72 h post-treatment despite the fact that ABZ was not detected in plasma and ABZSO and ABZSO2 were detected for only 30-36 h in plasma. The presence of ABZ and ABZSO in the abomasum and intestine for this extended period of time is probably relevant for anthelmintic efficacy against GI parasites. The NH2 ABZSO2 metabolite was detected in plasma, abomasum and ileum and its disposition kinetics were characterized for the first time.

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The effects of modulation of liver microsomal sulphoxidation on the disposition kinetics of netobimin (NTB) metabolites were investigated in sheep. A zwitterion suspension of NTB was given orally at 7.5 mg/kg to sheep either alone (control treatment) or co-administered with methimazole (MTZ) orally (NTB + MTZ oral treatment) or intra-muscularly (NTB + MTZ i.m.) at 3 mg/kg. Blood samples were taken serially over a 72 h period and plasma was analysed by HPLC for NTB and its major metabolites, i.e. albendazole (ABZ), albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2). Only trace amounts of NTB parent drug and ABZ were detected in the earliest samples after either treatment. There were significant modifications to the disposition kinetics of ABZSO in the presence of MTZ. ABZSO elimination half-life increased from 7.27 h (control treatment) to 14.57 h (NTB + MTZ oral) and to 11.39 h (NTB + MTZ i.m.). ABZSO AUCs were significantly higher (P less than 0.05) for the NTB + MTZ oral treatment (+55%) and for the NTB + MTZ i.m. treatment (+61%), compared with the NTB alone treatment. The mean residence times for ABZSO were 12.66 +/- 0.68 h (control treatment), 18.85 +/- 2.35 h (NTB + MTZ oral) and 17.02 +/- 0.90 h (NTB + MTZ i.m.). There were no major changes in the overall pharmacokinetics of ABZSO2 for the concomitant MTZ treatments. However, delayed appearance of this metabolite in the plasma resulted in longer ABZSO2 lag times and a delayed Tmax for treatments with MTZ.(ABSTRACT TRUNCATED AT 250 WORDS)