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ABSTRACT:The enantioselective sulfoxidation of the prochiral anthelmintic compounds albendazole (ABZ) and fenbendazole (FBZ) was investigated in liver, lung and small intestinal microsomes obtained from healthy sheep and cattle. The microsomal fractions were incubated with a 40 M concentration of either ABZ or FBZ. Inhibition of the flavin-containing monooxygenase (FMO) system was carried out by preincubation with 100 M methimazole (MTZ) either with or without heat pretreatment (2 min at 50°C). ABZ and FBZ were metabolized to the (؉) and (؊) enantiomers of their sulfoxide metabolites, named albendazole sulfoxide (ABZSO) and oxfendazole (OFZ), respectively. ABZ sulfoxidation rates were higher (p < 0.001) than those observed for FBZ. The FMO-mediated liver sulfoxidation of ABZ was enantioselective (100%) toward the (؉) ABZSO production in both species. Liver sulfoxidation of FBZ by FMO was also enantioselective toward (؉) OFZ (sheep ‫؍‬ 65%; cattle ‫؍‬ 79%). Cytochrome P450 was found to be mainly involved in the production of (؊) ABZSO in the liver. MTZ did not affect the sulfoxidation of ABZ by lung microsomes, which may indicate that FMO is not involved in the production of ABZSO in this tissue. A significant (p < 0.05) inhibition of (؊) ABZSO production by liver microsomes was observed after ABZ incubation in the presence of erythromycin (cattle ‫؍‬ 21%) and ketoconazole (sheep ‫؍‬ 36%). Both CYP3A substrates induced a reduction in the production of (؊) ABZSO (sheep ‫؍‬ 67-78%, cattle ‫؍‬ 50-78%) by lung microsomes. Overall, the results reported here contribute to the identification of the metabolic pathways involved in the biotransformation of benzimidazole anthelmintics extensively used for parasite control in ruminants.Livestock animals are exposed to a variety of xenobiotic agents (i.e., veterinary drugs, feed-additives, pesticides, pollutants, etc.) during their production cycles. These compounds are likely to be metabolized by different enzymatic systems from both hepatic and extrahepatic tissues. The metabolic activity of the flavin-containing monooxygenase (FMO) and cytochrome P450 (P450) systems plays a major role in determining the persistence of therapeutically used drugs in target species, which may additionally impose a risk to the consumer as a consequence of the permanence of drug residue levels in edible tissues. Metabolic interactions with either the FMO or P450 enzymatic systems may drastically affect the disposition kinetics of different drugs used in animal production, which will have a relevant impact on the pattern of drug/metabolite residues in edible tissues, a major concern for public health and consumer safety.Benzimidazole (BZD 1 ) and pro-BZD anthelmintics are extensively metabolized in domestic animals and humans. Their metabolic pattern and the resultant pharmacokinetic behavior are relevant in the attainment of high and sustained concentrations of pharmacologically active drug/metabolites at the target parasite . Albendazole (ABZ; methyl-[(5-propylthio)-1H-benzimidazol-2-yl] carba...

P-Glycoprotein (P-GP) is a transport protein that participates in the mechanism of active secretion of different molecules from the bloodstream to the gastrointestinal tract. The aim of the current work was to evaluate the effect of verapamil, a P-GP substrate, on the pharmacokinetic behaviour of the anthelmintics ivermectin and moxidectin in sheep. Thirty-two sheep were divided into four groups and treated orally with either ivermectin or moxidectin alone (200 micro g/kg) or co-administered with verapamil at 3 mg/kg (three times at 12 h intervals). Blood samples were collected over 30 days post-treatment and plasma was analysed to determine ivermectin and moxidectin concentrations by HPLC. The ivermectin peak concentration was significantly higher ( P=0.048) after ivermectin plus verapamil, compared with the ivermectin alone treatment. Ivermectin plasma availability was significantly higher following co-administration ( P=0.022). Verapamil had no effect on the kinetics of moxidectin. The significant alteration in the plasma disposition of ivermectin in sheep induced by verapamil, possibly due to interference with a P-GP-mediated elimination mechanism, may have an important impact on efficacy against resistant- or rate-limiting-parasites and on the persistency of its antiparasitic activity.

The effects of avermectin [ivermectin (IVM) and doramectin (DRM)] faecal residues on dung colonization and degradation by invertebrates were evaluated during late spring in the east of La Pampa province, Argentina. The study was conducted after collection of faecal material from animals (10 steers per group) allocated to the following groups: untreated control group (CG) and groups treated subcutaneously (200 μg/kg) with either DRM (DG) or a long‐acting formulation of IVM (IG). Fifty pats (550 g each) per group were collected, prepared and deposited on the field on days 3, 7, 16 and 29 post‐treatment (pt). Eight pats per group were recovered after 7, 14, 21, 42, 100 and 180 days post‐deposition (pd) on the field. The weight, percentage of dry matter, number of arthropods and nematodes from faeces were determined. The faecal concentrations of IVM and DRM were measured by high performance liquid chromatography (HPLC) throughout the trial period to correlate the pattern of drug degradation in dung with pd time. The total number of arthropods in dungs from CG was higher (P < 0.05) than those counted between days 3 and 29 pt in IG and DG. A decrease in the number of Coleoptera larvae (P < 0.05) between days 21 and 42 days pd was observed in both treated groups. Diptera larvae counts in CG pats were significantly higher (P < 0.05) than those obtained in treated groups in the 7‐ and 14‐day‐old pats. A lower number (P < 0.05) of Collembola, compared with pats from CG, was recovered from IG and DG pats deposited at days 3 and 7 pt and exposed from day 42. The counts of Acari in pats from treated animals were lower (P < 0.05) than those observed in CG pats at 3, 8 and 16 days pt. There were no differences neither in adult Scarabaeidae recovered nor in the proportions of dung buried and destroyed by great dung beetles. Dung specific nematodes were reduced (P < 0.05) in IG and DG pats from 3 and 7 days pt compared with those of CG pats. The comparative results shown here demonstrate that the negative effects of both IVM and DRM on dung colonization are similar. The pattern of drug degradation in the environment was very slow. High residual concentrations of both active parent compounds were recovered in dungs exposed in the field for up to 180 days pd. Concentrations as high as 13 ng/g (IVM) and 101 ng/g (DRM) were measured in faeces obtained from pats deposited on day 27 pt and exposed to the environment during 180 days. The results show a decrease in invertebrate colonization of dung recovered from IVM‐ and DRM‐treated cattle, which is in agreement with the large drug residual concentrations measured in faeces.

Triclabendazole (TCBZ) is an halogenated benzimidazole (BZD) compound worldwide used to control immature and adult stages of the liver fluke Fasciola hepatica. The purpose of this investigation was to characterize in vitro the patterns of hepatic and ruminal biotransformation of TCBZ and its metabolites in sheep. TCBZ parent drug was metabolized into its sulphoxide (TCBZSO), sulphone (TCBZSO2) and hydroxy derivatives by sheep liver microsomes. The same microsomal fraction was also able to oxidize TCBZSO into TCBZSO2 and hydroxy-TCBZSO (HO-TCBZSO). TCBZ sulphoxidation was significantly (P < 0.001) inhibited after inactivation of the flavin-monooxygenase (FMO) system (77% inhibition) as well as in the presence of the FMO substrate methimazole (MTZ) (71% inhibition). TCBZ sulphoxidative metabolism was also reduced (24% inhibition, P < 0.05) by the cytochrome P450 inhibitor piperonyl butoxide (PB). The rate of TCBZSO conversion into TCBZSO2 was also significantly inhibited by PB (55% inhibition), MTZ (52% inhibition) and also following FMO inactivation (58% inhibition). The data reported here indicate that the FMO is the main enzymatic pathway involved in TCBZ sulphoxidation (ratio FMO/P450 = 3.83 +/- 1.63), although both enzymatic systems participate in a similar proportion in the sulphonation of TCBZSO to form the sulphone metabolite (ratio FMO/P450 = 1.31 +/- 0.23). Additionally, ketoconazole (KTZ) did not affect TCBZ sulphoxidation but decreased (66% inhibition, P < 0.05) the formation of TCBZSO2. Similarly, inhibition of TCBZSO2 production was observed after incubation of TCBZSO in the presence of KTZ and erythromycin (ETM). Conversely, thiabendazole (TBZ) and fenbendazole (FBZ) did not affect the oxidative metabolism of both incubated substrates. The sheep ruminal microflora was able to reduce the sulphoxide (TCBZSO) into the parent thioether (TCBZ). The ruminal sulphoreduction of the HO-TCBZSO derivative into HO-TCBZ was also demonstrated. The rate of sulphoreduction of HO-TCBZSO was significantly (P < 0.05) higher than that observed for TCBZSO. The metabolic approach tested here contributes to the identification of the different pathways involved in drug biotransformation in ruminant species. These findings on the pattern of hepatic and ruminal biotransformation of TCBZ and its main metabolites are a further contribution to the understanding of the pharmacological properties of widely used anthelmintics in ruminants. Comprehension of TCBZ metabolism is critical to optimize its flukicidal activity.

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ABSTRACT:The everted gut sac method was used to assess the role of the P-glycoprotein (P-gp) on the intestinal secretion of ivermectin (IVM), an antiparasitic widely used in human and veterinary medicine. The work included the evaluation of two different P-gp modulators [itraconazole (ITZ) and valspodar (PSC833)] used at equimolar doses in the rat. Furthermore, the influence of both P-gp modulator agents on the disposition kinetics of IVM in plasma, liver, and gastrointestinal tissues was characterized.

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