methimazole and albendazole-sulfoxide

1. Precision-cut liver slices (PCLS) from food-producing animals have not been extensively used to study xenobiotic metabolism, and thus information on this field of research is sparse. 2. The aims of the present work were to further validate the technique of production and culture of bovine PCLS and to characterize the metabolic interaction between the anthelmintic albendazole (ABZ) and the flavin-monooxygenase (FMO) inhibitor methimazole (MTZ). 3. Nine steers were used as donors. PCLS were produced and incubated under two methods: a dynamic organ culture (DOC) incubator and a well-plate (WP) system. 4. Tissue viability, assessed through both structural and functional markers, was preserved throughout 12 h of incubation. ABZ was metabolized to its (+) and (-) albendazole sulfoxide stereoisomers (ABZSO) in bovine PCLS. The interaction between ABZ and MTZ resulted in a reduction (p < 0.001) in the rates of appearance of (+) ABZSO. Conversely, in presence of MTZ, the rates of appearance of (-) ABZSO increased under both systems (p < 0.05). 5. Both culture systems were suitable for assessing the interaction between ABZ and MTZ. 6. Overall, the results presented herein show that PCLS are a useful and reliable tool for short-term studies on metabolic drug-drug interactions in the bovine species.

Topics: Administration, Oral; Albendazole; Animals; Anthelmintics; Cattle; Drug Interactions; Liver; Methimazole; Microsomes, Liver; Stereoisomerism

1. The in vitro sulphoxidation of Albendazole (ABZ) by rat intestinal microsomes has been examined. The results revealed intestinal sulphoxidation of ABZ by intestinal microsomes in a NADPH-dependent enzymatic system. The kinetic constants for sulphoxidase activity were Vmax = 46 pmol/min/mg protein and Michaelis constant Km = 6.8 microM. 2. The possible effect of inducers (Arochlor 1254 and ABZ pretreatment) and inhibitors (erythromycin, methimazole, carbon monoxide and fenbendazole), was also studied. In rat pretreated with Arochlor 1254, Vmax was 52 pmol/min/mg protein, whereas oral administration of ABZ increased the intestinal sulphoxidation of the drug, Vmax being 103 pmol/min/mg protein. 3. Erythromycin did not change the enzymatic bioconversion of ABZ, but methimazole and carbon monoxide inhibited the enzyme activity by approximately 60 and 30% respectively. Fenbendazole (a structural analogue of ABZ) was a competitive inhibitor of the sulphoxidation process, characterized by a Ki or 69 microM. 4. These data demonstrate that the intestinal enzymes contributing to the initial sulphoxidation of ABZ may be similar to the hepatic enzymes involved in the biotransformation process by the P450 and FMO systems, a conclusion that needs to be further established.

Topics: Albendazole; Animals; Anthelmintics; Biotransformation; Carbon Monoxide; Enzyme Induction; Female; In Vitro Techniques; Intestine, Small; Methimazole; Microsomes; Mixed Function Oxygenases; NADP; Oxidation-Reduction; Rats; Rats, Wistar

1. The comparative rates of oxidation of the benzimidazole anthelmintic, albendazole (ABZ), by sheep and cattle liver microsomes, and inhibition by the antithyroid compound methimazole (MTZ) were investigated. 2. ABZ was oxidized to its sulphoxide metabolite (ABZSO) in an NADPH concentration-dependent reaction. Heat inactivation of the microsomal flavin-containing mono-oxygenase system significantly decreased the NADPH consumption of microsomes in the presence of ABZ, MTZ and thiourea. 3. Oxidation of ABZ, MTZ and thiourea by sheep liver microsomes consumed significantly more NADPH than oxidation by cattle microsomes. 4. Neither the pro-ABZ drug, netobimin, nor the ABZ sulphone metabolite (ABZSO2) was modified by incubation with either sheep or cattle liver microsomes. 5. ABZSO was oxidized into ABZSO2 at a very slow rate and only when a high microsomal protein concentration was used. 6. MTZ was a potent inhibitor of ABZ sulphoxidation and the inhibition was significantly lower in cattle than in sheep microsomes.

Topics: Albendazole; Animals; Binding Sites; Cattle; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme Inhibitors; In Vitro Techniques; Methimazole; Microsomes, Liver; NADP; Oxidation-Reduction; Oxygenases; Sheep; Sulfoxides; Thiourea

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

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