methimazole and netobimin

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)

Topics: Administration, Oral; Albendazole; Animals; Anthelmintics; Biotransformation; Chromatography, High Pressure Liquid; Female; Guanidines; Injections, Intramuscular; Methimazole; Sheep

The influence of methimazole (MTZ) on the pharmacokinetics of netobimin (NTB) and its metabolites was investigated in adult sheep. NTB zwitterion suspension was administered at 20 mg kg-1 by intraruminal injection either alone or with simultaneous administration of MTZ intramuscularly at 1.5 mg kg-1. Blood samples were taken serially over a 120-h period and plasma was analysed by HPLC for NTB, albendazole (ABZ), albendazole sulphoxide (ABZSO), and albendazole sulphone (ABZSO2). NTB parent drug showed fast absorption, low area under the plasma concentration-time curve (AUC) and was rapidly removed from plasma after both treatments. The presence of MTZ did increase significantly the ABZ AUC (138 per cent) and mean residence time (MRT) (86 per cent). Concomitant treatment with MTZ resulted in a notably higher ABZSO plasma profile with significantly longer elimination half-life (t1/2 beta) (390 per cent) and MRT (252 per cent) and with significantly higher AUC (95 per cent). Also, MTZ induced significant increases in ABZSO2 t1/2 beta, AUC, and MRT. We have demonstrated a pharmacokinetic interaction between MTZ and NTB metabolites. MTZ may alter the liver biotransformation of ABZ metabolites which results in pronounced changes in the disposition kinetics of anthelmintically active metabolites.

Topics: Albendazole; Animals; Anthelmintics; Biotransformation; Chromatography, High Pressure Liquid; Drug Interactions; Guanidines; Injections, Intramuscular; Male; Methimazole; Sheep

1. The effects of methimazole (MTZ) on the pharmacokinetic behaviour of netobimin (NTB) and its albendazole (ABZ) metabolites were studied in calves. NTB trisamine salt solution was given by subcutaneous (12.5 mg/kg) and oral (20 mg/kg) routes, either alone or co-administered with MTZ (1.5 mg/kg, intramuscularly). 2. NTB parent drug was detected only after s.c. treatments, showing rapid absorption, early Cmax and fast disposition. ABZ was not found in plasma at any time after either s.c. or oral treatments. 3. Concomitant treatment with MTZ significantly increased the albendazole sulphoxide (ABZSO) elimination half-life (t1/2 beta) (321%) and mean residence time (MRT) (170%) from the values obtained after s.c. treatment with NTB alone. 4. Oral treatment resulted in an ABZSO pharmacokinetic profile with an AUC 27% higher, a significantly longer t1/2 beta (151%) and MRT (124%) in the presence of MTZ. 5. We conclude that when co-administered with NTB in cattle, MTZ induces significant changes in the disposition kinetics of the anthelmintically active ABZSO metabolite.

Topics: Administration, Oral; Albendazole; Animals; Anthelmintics; Cattle; Guanidines; Half-Life; Injections, Subcutaneous; Kinetics; Methimazole; Sulfoxides

The effects of methimazole (MTZ), metyrapone (MTP) and quinine (QNE) on the pharmacokinetics and bioavailability of parenterally administered netobimin (NTB) and its major metabolites, albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2), were studied in sheep. NTB trisamine solution was first administered alone at 20 mg kg-1 by subcutaneous injection and then coadministered with either MTZ (1.5 mg kg-1 intramuscularly), MTP (20 mg kg-1 subcutaneously) or QNE (30 mg kg-1 intraruminally) in adult sheep. Blood samples were taken serially over a 120 hour period and plasma was analysed for NTB and its metabolites by high performance liquid chromatography. NTB parent drug showed a similar pharmacokinetic behaviour after all parenteral treatments. Both ABZSO AUCs (P less than 0.01) and Cmax (P less than 0.05) were significantly higher in the presence of MTZ and MTP than with the treatment with NTB alone. In the presence of each of the oxidation inhibitor compounds, the ratio of AUC ABZSO/ABZSO2 was significantly higher than with the NTB alone treatment. It has been demonstrated that the coadministration of substances which alter liver microsomal oxidation resulted in a modified pharmacokinetic pattern for the metabolites of NTB. Both NTB + MTZ and NTB + MTP treatments resulted in an improved pharmacokinetic profile for the anthelmintically active ABZSO metabolite.

Topics: Albendazole; Animals; Anthelmintics; Drug Interactions; Guanidines; Injections, Intramuscular; Injections, Subcutaneous; Liver; Male; Methimazole; Metyrapone; Oxidation-Reduction; Oxidoreductases; Quinine; Sheep