Monepantel-based anthelmintic combinations to optimize parasite control in cattle.

Improvement in the use of existing anthelmintics is a high priority need for the pharmaco-parasitology research field, considering the magnitude and severity of anthelmintic resistance as an important issue in livestock production. In the work described here, monepantel (MNP) was given alone or co-administered with either macrocyclic lactone (ML) or benzimidazole (BZ) anthelmintics to calves naturally infected with ML- and BZ-resistant gastrointestinal (GI) nematodes on two different commercial cattle farms. Both pharmacokinetic (PK) and efficacy assessments were performed. On Farm A, male calves (n = 15 per group) were treated with either MNP orally (2.5 mg/kg), IVM s.c. (0.2 mg/kg), ricobendazole (RBZ) s.c. (3.75 mg/kg) or remained untreated. On Farm B, eight groups (n = 15) of male calves received treatment with either: MNP, abamectin (ABM, oral, 0.2 mg/kg), RBZ (s.c., 3.75 mg/kg), albendazole (ABZ, oral, 5 mg/kg), MNP+ABM, MNP+RBZ, MNP+ABZ (all at the above-mentioned routes and doses) or remained untreated. Seven animals from each treated group (Farm B) were randomly selected to perform the PK study. MNP and its metabolite monepantel sulphone (MNPSO2) were the main analytes recovered in plasma after HPLC analysis. The combined treatments resulted in decreased systemic exposures to MNP parent drug compared with that observed after treatment with MNP alone (P < 0.05). However, the systemic availability of the main MNP metabolite (MNPSO2) was unaffected by co-administration with either ABM, RBZ or ABZ. Efficacies of 98% (Farm A) and 99% (Farm B) demonstrated the high efficacy of MNP given alone (P < 0.05) against GI nematodes resistant to ML and BZ in cattle. While the ML (IVM, ABM) failed to control Haemonchus spp., Cooperia spp. and Ostertagia spp., MNP achieved 99% to 100% efficacy against those nematode species on both commercial farms. However, MNP alone failed to control Oesophagostomum spp. (60% efficacy) on Farm A. The co-administered treatments MNP+ABZ and MNP+RBZ reached a 100% reduction against all GI nematode genera. In conclusion, the oral treatment with MNP should be considered to deal with resistant nematode parasites in cattle. The use of MNP in combination with BZ compounds could be a valid strategy to extend its lifespan for use in cattle as well as to reverse its poor activity against Oesophagostomum spp.

ABC-transporter gene expression in ivermectin-susceptible and resistant Haemonchus contortus isolates.

Mammalian efflux transporters of the ATP-binding cassette (ABC) regulate cellular levels of endo- and xenobiotics by transporting molecules across cell membranes and are involved in diverse biological processes. Over-expression of these ABC transporters has been involved in macrocyclic lactone resistance. The main goal of this work was to compare the gene expression of the whole ABC-transporter superfamily in isolates of the sheep nematode Haemonchus contortus with different degrees of susceptibility to ivermectin (IVM). Additionally, the effects of in vivo IVM treatment were evaluated in the resistant isolates. Parasite-free Corriedale lambs were artificially infected with either IVM-susceptible or IVM-resistant H. contortus isolates. The differential expression of ABC transcripts in H. contortus female worms with differential susceptibility to IVM were assessed by RNA-seq. Additionally, the transcription levels of ABC-transporter genes in IVM-resistant adult worms recovered from treated sheep at 12 and 24 h after IVM administration were compared to those of IVM-R worms collected from untreated sheep. The comparative analysis of the ABC-transcripts revealed some minor differences in the expression levels of HCON_00042800 (pgp-3), HCON_00020200.mod (ced-7c), HCON_00085890 (abt-4), HCON_00063000 (pmp-5) and HCON_00116670 (wht-8), indicating that, at transcriptional level, these ABC-genes alone cannot explain resistance in H. contortus. HCON_00130060 (pgp-9.2) was highly differentially expressed in resistant isolates compared to susceptible ones, which agrees with previous reports suggesting that pgp-9 may be one of the most relevant candidates contributing to the multi-genic nature of the IVM resistance trait.

Pharmacokinetics and milk excretion pattern of eprinomectin at different dose rates in dairy cattle.

This study aimed at determining the plasma disposition kinetics of eprinomectin (EPM) and EPM excretion pattern through milk after topical administration to dairy cattle at the recommended dose of 0.5 mg/kg and at 1 and 1.5 mg/kg. A high variability in the plasma concentration profiles was observed among animals, particularly in the Cmax values, with a coefficient of variation between 39 and 53%. The Cmax and AUC values were significantly affected by the dose administered at 1.5 mg/kg. However, such differences did not seem to follow a linear pattern among treatments. These parameters did not differ among dose rates after dose normalization; nevertheless, the simulation of a linear kinetic disposition showed a mean plasma AUC value of 254 ng.d/ml instead of the observed value of 165 ng.d/ml. EPM concentration profiles in milk were significantly lower than those measured in plasma. The Cmax and AUC milk-to-plasma ratios ranged from 0.14 to 0.26 and 0.16 to 0.21, respectively (p>0.05). The low milk-to-plasma ratio of EPM accounted for a low percentage of the fraction of the administered dose excreted through milk, being significantly higher at a dose rate of 0.5 mg/kg (0.07%) of EPM than at 1.5 mg/kg (0.04%) (p<0.05). The topical administration of EPM to lactating dairy cows at higher doses than that recommended for gastrointestinal nematodes showed a milk excretion pattern with a zero milk withdrawal period. In conclusion, the administration of topical EPM formulation at 1 or 1.5 mg/kg may be a valuable tool to be used in regional strategic deworming programs aimed to control ectoparasite infections in dairy production systems.

Monepantel pharmaco-therapeutic evaluation in cattle: Pattern of efficacy against multidrug resistant nematodes.

The goal of the current work was to perform an integrated evaluation of monepantel (MNP) pharmacokinetics (PK) and pharmacodynamics, measured as anthelmintic efficacy, after its oral administration to calves naturally infected with GI nematodes resistant to ivermectin (IVM) and ricobendazole (RBZ) on three commercial farms. On each farm, forty-five calves were randomly allocated into three groups (n = 15): MNP oral administration (2.5 mg/kg); IVM subcutaneous (SC) administration (0.2 mg/kg); and RBZ SC administration (3.75 mg/kg). Eight animals from the MNP treated group (Farm 1) were selected to perform the PK study. Drug concentrations were measured by HPLC. The efficacy was determined by the faecal egg count reduction test (FECRT). MNP and MNP-sulphone (MNPSO2) were the main analytes recovered in plasma. MNPSO2 systemic exposure was markedly higher compared to that obtained for MNP. Higher Cmax and AUC values were obtained for the active MNPSO2 metabolite (96.8 ± 29.7 ng/mL and 9220 ± 1720 ng h/mL) compared to MNP (21.5 ± 4.62 ng/mL and 1709 ± 651 ng h/mL). The MNPSO2 AUC value was 6-fold higher compared to the parent drug. Efficacies of 99% (Farm 1), 96% (Farm 2) and 98% (Farm 3) demonstrated the high activity of MNP (P < 0.05) against GI nematodes resistant to IVM (reductions between 27 and 68%) and RBZ (overall efficacy of 75% on Farm 3). While IVM failed to control Haemonchus spp. and Cooperia spp., and RBZ failed to control Coooperia spp. and Ostertagia spp., MNP achieved 100% efficacy against Haemonchus spp., Cooperia spp. and Ostertagia spp. However, a low efficacy of MNP against Oesophagostomum spp. (efficacies ranging from 22 to 74%) was observed. In conclusion, oral treatment with MNP should be considered for dealing with IVM and benzimidazole resistant nematode parasites in cattle. The work described here reports for the first time an integrated assessment of MNP pharmaco-therapeutic features and highlights the need to be considered as a highly valuable tool to manage nematode resistant to other chemical families.

Safety and Pharmacokinetic Assessments of a Novel Ivermectin Nasal Spray Formulation in a Pig Model.

Recently published data indicates that high ivermectin (IVM) concentrations suppress in vitro SARS-CoV-2 replication. Nasal IVM spray administration may contribute to attaining high drug concentrations in nasopharyngeal tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performances of a novel IVM spray formulation were assessed in a pig model. Piglets received IVM either orally (0.2 mg/kg) or by one or two nasal spray doses. The overall safety, and histopathology of the IVM-spray application site tissues, were assessed. The IVM concentration profiles measured in plasma and respiratory tract tissues after the nasal spray were compared with those achieved after the oral administration. Animals tolerated well the nasal spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in nasopharyngeal and lung tissues. The nasal/oral IVM concentration ratios in nasopharyngeal and lung tissues markedly increased by repeating (12 h apart) the spray application. The fast attainment of high and persistent IVM concentrations in nasopharyngeal tissue is the main advantage of the nasal over the oral route. These original results support the undertaking of future clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the prevention and/or treatment of COVID-19.

Relationship between pharmacokinetics of ivermectin (3.15%) and its efficacy to control the infestation with the tick Rhipicephalus (Boophilus) microplus in cattle.

This study aimed to determine the relationship between the variation in plasma concentration of ivermectin 3.15% over time and its efficacy against the cattle tick Rhipicephalus (Boophilus) microplus. In addition, a trial was conducted to infer if the application of successive treatments with ivermectin 3.15% could affect its accumulation in cattle. A noticeable variation of ivermectin plasma concentration was observed among the treated heifers. However, these differences did not have a significant effect onthe therapeutic efficacy of the treatment at the end of the trial. No significant differences were observed in the levels of tick infestations between heifers of the treated group; moreover, no significant correlation was detected between the plasma AUC0-21 of ivermectin 3.15% and the cumulative number of ticks of each heifer. Levels of therapeutic efficacy higher than 80% were observed only from day 7 post-treatment, when levels of ivermectin concentration were higher than 8 ng/ml. The lowest values of therapeutic efficacy were observed during the first and the second days post-treatment, when plasma concentrations of ivermectin 3.15% were lower than 8 ng/ml. Viable engorged females were collected from the heifers belonging to the treated group from days 1-5 post-treatment. There was a significant accumulation of the drug after the second dose of ivermectin 3.15%. Ivermectin concentrations in fat biopsies were 366 ng/g (51 days after the first treatment), 275 ng/g (51 days after the second treatment) and 15 ng/g (64 days after the second treatment). These results suggest that applications of successive treatments with ivermectin 3.15% might increase its accumulation in cattle tissues, extending the withdrawal period indicated for the commercial formulation.

Role of ABC Transporters in Veterinary Medicine: Pharmaco- Toxicological Implications.

Unlike physicians, veterinary practitioners must deal with a number of animal species with crucial differences in anatomy, physiology and metabolism. Accordingly, the pharmacokinetic behaviour, the clinical efficacy and the adverse or toxic effects of drugs may differ across domestic animals. Moreover, the use of drugs in food-producing species may impose a risk for humans due to the generation of chemical residues in edible products, a major concern for public health and consumer's safety. As is clearly known in human beings, the ATP binding cassette (ABC) of transport proteins may influence the bioavailability and elimination of numerous drugs and other xenobiotics in domestic animals as well. A number of drugs, currently available in the veterinary market, are substrates of one or more transporters. Therefore, significant drug-drug interactions among ABC substrates may have unpredictable pharmacotoxicological consequences in different species of veterinary interest. In this context, different investigations revealed the major relevance of P-gp and other transport proteins, like breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), in both companion and livestock animals. Undoubtedly, the discovery of the ABC transporters and the deep understanding of their physiological role in the different species introduced a new paradigm into the veterinary pharmacology. This review focuses on the expression and function of the major transport proteins expressed in species of veterinary interest, and their impact on drug disposition, efficacy and toxicity.

Assessment of the long-acting ivermectin formulation in sheep: Further insight into potential pharmacokinetic interactions.

The aim of the current study was to evaluate the in vivo pharmacokinetic of ivermectin (IVM) after the administration of a long-acting (LA) formulation to sheep and its impact on potential drug-drug interactions. The work included the evaluation of the comparative plasma profiles of IVM administered at a single therapeutic dose (200 µg/kg) and as LA formulation at 630 µg/kg. Additionally, IVM was measured in different gastrointestinal tissues at 15 days posttreatment with both IVM formulations. The impact of the long-lasting and enhanced IVM exposure on the disposition kinetics of abamectin (ABM) was also assessed. Plasma (IVM and ABM) and gastrointestinal (IVM) concentrations were analyzed by HPLC with fluorescent detection. In plasma, the calculated Cmax and AUC0-t values of the IVM-LA formulation were 1.47- and 3.35-fold higher compared with IVM 1% formulation, respectively. The T1/2ab and Tmax collected after administration of the LA formulation were 2- and 3.5-fold longer than those observed after administration of IVM 1% formulation, respectively. Significantly higher IVM concentrations were measured in the intestine mucosal tissues and luminal contents with the LA formulation, and in the liver, the increase was 7-fold higher than conventional formulation. There was no drug interaction between IVM and ABM after the single administration of ABM at 15 days post-administration of the IVM LA formulation. The characterization of the kinetic behavior of the LA formulation to sheep and its potential influence on drug-drug interactions is a further contribution to the field.

The ABCG2 Efflux Transporter in the Mammary Gland Mediates Veterinary Drug Secretion across the Blood-Milk Barrier into Milk of Dairy Cows.

In human and mice ATP-binding cassette efflux transporter ABCG2 represents the main route for active drug transport into milk. However, there is no detailed information on the role of ABCG2 in drug secretion and accumulation in milk of dairy animals. We therefore examined ABCG2-mediated drug transport in the bovine mammary gland by parallel pharmacokinetic studies in lactating Jersey cows and in vitro flux studies using the anthelmintic drug monepantel (MNP) as representative bovine ABCG2 (bABCG2) drug substrate. Animals received MNP (Zolvix, Novartis Animal Health Inc.) once (2.5 mg/kg per os) and the concentrations of MNP and the active MNP metabolite MNPSO2 were assessed by high-performance liquid chromatography. Compared with the parent drug MNP, we detected higher MNPSO2 plasma concentrations (expressed as area under the concentration-versus-time curve). Moreover, we observed MNPSO2 excretion into milk of dairy cows with a high milk-to-plasma ratio of 6.75. In mechanistic flux assays, we determined a preferential time-dependent basolateral-to-apical (B > A) MNPSO2 transport across polarized Madin-Darby canine kidney II cells-bABCG2 monolayers using liquid chromatography coupled with tandem mass spectrometry analysis. The B > A MNPSO2 transport was significantly inhibited by the ABCG2 inhibitor fumitremorgin C in bABCG2- but not in mock-transduced MDCKII cells. Additionally, the antibiotic drug enrofloxacin, the benzimidazole anthelmintic oxfendazole and the macrocyclic lactone anthelmintic moxidectin caused a reduction in the MNPSO2(B > A) net efflux. Altogether, this study indicated that therapeutically relevant drugs like the anthelmintic MNP represent substrates of the bovine mammary ABCG2 transporter and may thereby be actively concentrated in dairy milk.

Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels.

The main goals of the current work were: (a) to assess the ivermectin (IVM) systemic exposure and plasma disposition kinetics after its administration at the recommended dose, x5 and x10 doses to lambs, (b) to compare the clinical efficacy of the same IVM dosages in lambs infected with an IVM-resistant isolate of Haemonchus contortus, and (c) to assess the expression of the transporter protein P-glycoprotein (P-gp) in H. contortus recovered at 14 days after administration of the IVM dose regimens. There were two separated trials where IVM was administered either subcutaneously (SC, Experiment I) or intraruminally (IR, Experiment II). Each experiment involved twenty-four (24) lambs artificially infected with a highly resistant H. contortus isolate. Animals were allocated into 4 groups (n=6) and treated with IVM at either 0.2 (IVM x1), 1 (IVM x5) or 2mg/kg (IVM x10). Plasma samples were collected up to 12 days post-treatment and analysed by HPLC. An untreated-control Group was included to assess the comparative anthelmintic efficacy of the different treatments. The level of expression of Pgp in H. contortus specimens obtained from lambs both untreated and IR treated with the different IVM doses was quantified by real time PCR. Parametric and non-parametric tests were used to compare the statistical significance of the results (P<0.05). After the SC treatment, the IVM plasma area under the concentration-time curve (AUC0-LOQ) increased from 41.9 (IVM SCx1) up to 221 (IVM SCx5) and 287 (IVM SCx10)ng.day/mL and after the IR treatment from 20.8 (IVM IRx1) up to 121 (IVM IRx5) and 323 (IVM IRx10)ng.day/mL. Dose-adjusted AUC0-LOQ and Cmax were similar among doses, demonstrating dose proportionality for IVM after both SC and IR administration at the three different doses. The efficacies against resistant H. contortus after the SC treatment were 42% (IVM SC1), 75% (IVM SCx5) and 75% (IVM SCx10). However, the IR IVM treatment reached clinical efficacies ranging from 48% (IVM IRx1) up to 96% (IVM IRx5) and 98% (IVM IRx10). None of the IR IVM treatments increased the expression of P-gp in adult H. contortus at 14 days post-treatment compared to samples collected from the untreated control group. An enhanced parasite exposure of the drug at the abomasum may explain the improved efficacy against this recalcitrant H. contortus isolate observed only after the IR administration at 5- and 10-fold the IVM therapeutic dosage.

Gene expression and enzyme function of two cytochrome P450 3A isoenzymes in rat and cattle precision cut liver slices.

1. Precision-cut liver slices are one of the in vitro models used in studies concerning xenobiotic metabolism. Sparse information on this field is actually available for cattle and other veterinary species. 2. The aim of the current work was to study the effect of dexamethasone (DEX) on the gene expression and function of CYP3A23 (in rat), CYP3A28 (in cattle) and the transcriptional factors involved in their regulation. 3. DEX (at 100 µM) up-regulated CYP3A23 mRNA (3.2-fold, p = 0.028) in rat liver slices after 12 h culture, whereas the gene expression profiles of transcriptional factors involved in CYP3A regulation were unaffected. A CYP3A-dependent enzyme activity (triacetyl-oleandomycin N-demethylase) increased 3.4-fold (p < 0.05) in rat liver slices cultured in the presence of DEX. 4. The protocol used for rat liver slices was used as reference to study the expression of a CYP3A isoenzyme in cattle liver slices. Oppositely, DEX did neither affect the gene expression profile of CYP3A28 nor the CYP3A activity tested in cattle liver slices. 5. The data reported here are a further contribution to demonstrate the usefulness of liver slices as an in vitro tool for studies on the expression and function of xenobiotic metabolizing enzymes in cattle and in other ruminant species.

Comparative tissue pharmacokinetics and efficacy of moxidectin, abamectin and ivermectin in lambs infected with resistant nematodes: Impact of drug treatments on parasite P-glycoprotein expression.

The high level of resistance to the macrocyclic lactones has encouraged the search for strategies to optimize their potential as antiparasitic agents. There is a need for pharmaco-parasitological studies addressing the kinetic-dynamic differences between various macrocyclic lactones under standardized in vivo conditions. The current work evaluated the relationship among systemic drug exposure, target tissue availabilities and the pattern of drug accumulation within resistant Haemonchus contortus for moxidectin, abamectin and ivermectin. Drug concentrations in plasma, target tissues and parasites were measured by high performance liquid chromatography. Additionally, the efficacy of the three molecules was evaluated in lambs infected with resistant nematodes by classical parasitological methods. Furthermore, the comparative determination of the level of expression of P-glycoprotein (P-gp2) in H. contortus recovered from lambs treated with each drug was performed by real time PCR. A longer persistence of moxidectin (P < 0.05) concentrations in plasma was observed. The concentrations of the three compounds in the mucosal tissue and digestive contents were significant higher than those measured in plasma. Drug concentrations were in a range between 452 ng/g (0.5 day post-treatment) and 32 ng/g (2 days post-treatment) in the gastrointestinal (GI) contents (abomasal and intestinal). Concentrations of the three compounds in H. contortus were in a similar range to those observed in the abomasal contents (positive correlation P = 0.0002). Lower moxidectin concentrations were recovered within adult H. contortus compared to abamectin and ivermectin at day 2 post-treatment. However, the efficacy against H. contortus was 20.1% (ivermectin), 39.7% (abamectin) and 89.6% (moxidectin). Only the ivermectin treatment induced an enhancement on the expression of P-gp2 in the recovered adult H. contortus, reaching higher values at 12 and 24 h post-administration compared to control (untreated) worms. This comparative pharmacological evaluation of three of the most used macrocyclic lactones compounds provides new insights into the action of these drugs.

In vivo and ex vivo assessment of the interaction between ivermectin and danofloxacin in sheep.

The impact of an efflux pump-related interaction between ivermectin and danofloxacin on their intestinal transport (ex vivo) and disposition kinetics (in vivo) was assessed. Eighteen male Corriedale sheep were randomly assigned to one of three groups. Animals in Group A received 0.2mg/kg ivermectin by SC injection, those in Group B were given 6 mg/kg danofloxacin SC on two occasions 48 h apart and those in Group C were treated with both compounds at the same rates. Plasma concentrations of ivermectin and danofloxacin were measured by HPLC using fluorescence detection. Ex vivo intestinal drug transport activity was measured by the use of the Ussing chamber technique. Plasma concentrations of ivermectin in the first 6 days after injection tended to be higher in Group C than Group A. Contemporaneous treatment with ivermectin significantly increased systemic exposure to danofloxacin (AUC values were 32-35% higher) and prolonged the elimination half-life of danofloxacin (40-52% longer). Ex vivo, incubation with ivermectin significantly decreased the efflux transport of rhodamine 123, a P-glycoprotein substrate, in sheep intestine, but no significant effect of danofloxacin on transport activity was observed. Evaluation of the interaction of danofloxacin with the breast cancer resistance protein (BCRP) showed that pantoprazole and ivermectin significantly decreased danofloxacin secretion in the rat intestine. Thus, the ivermectin-induced reduction of danofloxacin efflux transport observed in this study may involve BCRP activity but the involvement of P-glycoprotein cannot be ruled out.

Combined use of ivermectin and triclabendazole in sheep: in vitro and in vivo characterisation of their pharmacological interaction.

This study evaluated the pharmacokinetic properties of ivermectin (IVM) and triclabendazole (TCBZ) given either separately or co-administered to sheep. Corriedale sheep received IVM alone, TCBZ alone or a combination of IVM and TCBZ intravenously. Ivermectin elimination was delayed and its plasma availability was 3-fold higher when co-administered with TCBZ. Similarly, plasma concentrations of TCBZ and its metabolites were influenced by the co-administration of IVM. Higher peak plasma concentrations of TCBZ metabolites were detected after the co-administration of TCBZ and IVM compared to those obtained following TCBZ treatment in isolation. Complementary in vitro assays were carried out to assess the influence of TCBZ on the P-glycoprotein-mediated intestinal transport of IVM, using the everted gut sac technique. Enhanced accumulation of IVM in the intestinal wall occurred after co-incubation with TCBZ.

Hepatic and extra-hepatic metabolic pathways involved in flubendazole biotransformation in sheep.

Flubendazole (FLBZ) is a broad-spectrum benzimidazole anthelmintic compound used in pigs, poultry and humans. Its potential for parasite control in ruminant species is under investigation. The objective of the work described here was to identify the main enzymatic pathways involved in the hepatic and extra-hepatic biotransformation of FLBZ in sheep. Microsomal and cytosolic fractions obtained from sheep liver and duodenal mucosa metabolised FLBZ into a reduced FLBZ metabolite (red-FLBZ). The keto-reduction of FLBZ led to the prevalent (approximately 98%) stereospecific formation of one enantiomeric form of red-FLBZ. The amounts of red-FLBZ formed in liver subcellular fractions were 3-4-fold higher (P<0.05) compared to those observed in duodenal subcellular fractions. This observation correlates with the higher (P<0.05) carbonyl reductase (CBR) activities measured in the liver compared to the duodenal mucosa. No metabolic conversion was observed following FLBZ or red-FLBZ incubation with sheep ruminal fluid. Sheep liver microsomes failed to convert red-FLBZ into FLBZ. However, this metabolic reaction occurred in liver microsomes prepared from phenobarbital-induced rats, which may indicate a cytochrome P450-mediated oxidation of red-FLBZ. A NADPH-dependent CBR is proposed as the main enzymatic system involved in the keto-reduction of FLBZ in sheep. CBR substrates such as menadione and mebendazole (a non-fluoride analogue of FLBZ), inhibited this liver microsomal enzymatic reaction, which may confirm the involvement of a CBR enzyme in FLBZ metabolism in sheep. This research is a further contribution to the understanding of the metabolic fate of a promissory alternative compound for antiparasitic control in ruminant species.