Pharmacokinetic assessment of the monepantel plus oxfendazole combined administration in dairy cows

Ballent, Mariana; Viviani, P.; Imperiale, F.; Domínguez, Paula Revenga; Halwachs, Sandra; Mahnke, Hanna; Honscha, Walther; Lanusse, Carlos; Virkel, G.; Lifschitz, Adrián Luis

doi:10.1111/jvp.12466

Cited by 8 publications

(11 citation statements)

References 42 publications

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“…The MNP plasma disposition kinetics has not been described in beef cattle. However, in line with previous PK studies in sheep ( Karadzovska et al, 2009 ; Lifschitz et al, 2014 ) and dairy cows ( Ballent et al, 2017 ), a rapid decline in the plasma profiles of the parent drug and the recovery of the MNPSO 2 metabolite as the main analyte detected in the bloodstream, were observed in beef calves in the current trial. The metabolic conversion of MNP into MNPSO 2 also involves the production of an intermediate sulphoxide derivative ( Karadzovska et al, 2009 ), which is rapidly and almost completely converted into MNPSO 2 , being undetectable in plasma of MNP treated animals.…”

Section: Discussionsupporting

confidence: 89%

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

Cantón

Lifschitz

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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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 (MNPSO 2 ) were the main analytes recovered in plasma. MNPSO 2 systemic exposure was markedly higher compared to that obtained for MNP. Higher Cmax and AUC values were obtained for the active MNPSO 2 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 MNPSO 2 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.

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Section: Discussionsupporting

confidence: 89%

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

Cantón

Lifschitz

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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“…The percentage of the total administered dose recovered from milk was reported as 0.09% (MNP) and 2.79% (MNPSO 2 ) after the administration of MNP alone and 0.06% (MNP) and 2.34% (MNPSO 2 ) after the combined treatment. However, the presence of MNP does not alter the plasma and milk excretion kinetics of OFZ (Ballent et al, 2018). In our study, the percentage of the total administered dose recovered from milk was 0.08% (MNP) and 2.6% (MNPSO 2 ) in MNP group, 0.03% (MNP) and 2.12% (MNPSO 2 ) in MNP + Soy group, and 0.06% (MNP) and 2.22% (MNPSO 2 ) in MNP + GEN‐DAI group.…”

Section: Discussionmentioning

confidence: 99%

“…The average milk production was 0.55 L/animal/day. Using the following equation, the percentage of drug elimination into milk was calculated below (Ballent et al, 2018).

% dose excreted into milk = (V_{milk} \times C_{milk} / D) \times 100

V milk is the individual milk production (ml); C milk is the drug concentration in milk (μg/ml), and D is the total administered dose (mg).…”

Section: Methodsmentioning

confidence: 99%

Modulation of monepantel secretion into milk by soy isoflavones

GÜNEŞ>

Okyar

Krajcsi

et al. 2022

Vet Pharm & Therapeutics

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Monepantel (MNP), a novel anthelmintic drug from amino‐acetonitrile derivatives, is a substrate for breast cancer resistance protein (BCRP). BCRP‐mediated milk secretion of drugs can be altered by isoflavones. In this study, we aimed to show how soy isoflavones and BCRP inhibitors genistein (GEN) and daidzein (DAI) can modulate the secretion of MNP into milk. Moreover, we observed that the expression of BCRP in the lactating mammary gland of sheep was significantly higher than in non‐lactating sheep using Western blot analysis. These properties of MNP and MNPSO2 (monepantel sulfone, the major active metabolite of MNP), identified as a BCRP substrate in determining the interaction with BCRP, were examined by vesicular transport (VT) inhibition assays. In pharmacokinetic studies, we demonstrated the transport of MNP into milk in three experimental groups: G1 fed standard forage; G2 fed soy‐enriched forage; G3 fed standard forage paired with orally administered exogenous GEN and DAI. The concentrations of MNP and MNPSO2 were analyzed by high‐performance liquid chromatography. Compared to the control group (3.27 ± 1.13 vs. 5.46 ± 2.23), the AUC (0–840 h) milk/plasma ratio decreased by 40% in the soy‐enriched diet group. The concentrations of GEN and DAI were determined using liquid chromatography coupled with tandem mass spectrometry in soy. A VT inhibition assay was conducted to determine the IC50 values for MNP and MNPSO2 as BCRP inhibitors. This study showed that milk excretion of a BCRP substrate, such as monepantel, can be diminished by the presence of isoflavones in the diet.

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“…Previous studies have been conducted to determine interaction between ecto/endoparasitic drugs and OFZ after different administration routes in different species. It was reported that orally administered monepantel did not change the plasma kinetics of OFZ in dairy cows (Ballent et al, 2018) and orally administered piperonyl butoxide inhibited the biotransformation of intravenously administered OFZ in horses (Sánchez et al, 2002). In horses treated with the combination of piperonyl butoxide and OFZ, the plasma concentration of OFZ was increased and this increase was reflected in a significantly higher AUC values and longer MRT.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and pharmacokinetic interactions of orally administered oxfendazole and oxyclozanide tablet formulation to sheep

Kutahya

Kandir

Faki

et al. 2022

Vet Pharm & Therapeutics

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The combination of oxfendazole and oxyclozanide is used to provide activity against fluke and gastrointestinal nematodes. This study aimed to determine both the pharmacokinetics of oxfendazole (7.5 mg/kg) and oxyclozanide (15 mg/kg) tablet formulation administered orally to sheep and whether there is a pharmacokinetic interaction between these two drugs. The study was conducted in a three-period, crossover pharmacokinetic design and on six healthy Awassi sheep 1-3 years of age.The plasma concentrations of oxfendazole and its metabolites (fenbendazole and fenbendazole sulphone) and oxyclozanide were determined by high-performance liquid chromatography using an ultraviolet detector. Compounds recovered in plasma when oxfendazole was administered alone or combined with oxyclozanide were oxfendazole, fenbendazole sulphone, and fenbendazole, respectively. When oxfendazole was administered alone and co-administered with oxyclozanide, the AUC FBZ / AUC OFZ was 0.26 and 0.23, respectively, and the AUC FBZSO2 /AUC OFZ was 0.35 and 0.32, respectively. The volume of distribution (Vz/F) of oxfendazole was large in both groups. Oxyclozanide did not change the plasma disposition of oxfendazole.When the oxyclozanide tablet formulation was administered alone, the elimination half-life (21.35 h) and the Vz/F (940.17 ml/kg) were long and large, respectively. The area under the curve (AUC) and the maximum plasma concentration of oxyclozanide were significantly larger and higher, respectively, in the oxyclozanide plus oxfendazole group (1146.61 h × μg/ml and 29.80 μg/ml) compared with the oxyclozanide group (491.44 h × μg/ml and 14.24 μg/ml) while a significant decrease in apparent Vz/F (940.17 vs 379.14 ml/kg) and total clearance (30.52 vs 13.08 ml/h/kg) was detected.In conclusion, co-administration with oxfendazole causing an increase in the plasma profile of oxyclozanide may increase the antiparasitic activity of oxyclozanide.

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Pharmacokinetic assessment of the monepantel plus oxfendazole combined administration in dairy cows

Cited by 8 publications

References 42 publications

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

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

Modulation of monepantel secretion into milk by soy isoflavones

Pharmacokinetics and pharmacokinetic interactions of orally administered oxfendazole and oxyclozanide tablet formulation to sheep

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