Plasma and milk kinetic of eprinomectin and moxidectin in lactating water buffaloes (Bubalus bubalis)

doi:10.1016/j.vetpar.2008.07.027

Veterinary Parasitology

Volume 157, Issues 3–4, 7 November 2008, Pages 284-290

https://doi.org/10.1016/j.vetpar.2008.07.027 Get rights and content

Abstract

The pharmacokinetics and mammary excretion of moxidectin and eprinomectin were determined in water buffaloes (Bubalus bubalis) following topical administration of 0.5 mg kg⁻¹. Following administration of moxidectin, plasma and milk concentrations of moxidectin increased to reach maximal concentrations (C_max) of 5.46 ± 3.50 and 23.76 ± 16.63 ng ml⁻¹ at T_max of 1.20 ± 0.33 and 1.87 ± 0.77 days in plasma and milk, respectively. The mean residence time (MRT) were similar for plasma and milk (5.27 ± 0.45 and 5.87 ± 0.80 days, respectively). The AUC value was 5-fold higher in milk (109.68 ± 65.01 ng day ml⁻¹) than in plasma (23.66 ± 12.26 ng day ml⁻¹). The ratio of AUC milk/plasma for moxidectin was 5.04 ± 2.13. The moxidectin systemic availability (expressed as plasma AUC values) obtained in buffaloes was in the same range than those reported in cattle. The faster absorption and elimination processes of moxidectin were probably due to a lower storage in fat associated with the fact that animals were in lactation. Nevertheless, due to its high excretion in milk and its high detected maximum concentration in milk which is equivalent or higher to the Maximal Residue Level value (MRL) (40 ng ml⁻¹), its use should be prohibited in lactating buffaloes.

Concerning eprinomectin, the C_max were of 2.74 ± 0.89 and 3.40 ± 1.68 ng ml⁻¹ at T_max of 1.44 ± 0.20 and 1.33 ± 0.0.41 days in plasma and milk, respectively. The MRT and the AUC were similar for plasma (3.17 ± 0.41 days and 11.43 ± 4.01 ng day ml⁻¹) and milk (2.70 ± 0.44 days and 8.49 ± 3.33 ng day ml⁻¹). The ratio of AUC milk/plasma for eprinomectin was 0.76 ± 0.16. The AUC value is 20 times lower than that reported in dairy cattle. The very low extent of mammary excretion and the milk levels reported lower than the MRL (20 ng ml⁻¹) supports the permitted use of eprinomectin in lactating water buffaloes.

Introduction

Water buffalo (Bubalus bubalis) represent a ruminant species important in the economy of several countries, including Brazil, India, Vietnam and some regions of central and southern Italy, where the breed Mediterranean Italian buffalo produces high quality milk employed for production of the buffalo “mozzarella”, a fresh cheese with a protected designation of origin (PDO) according to EU legislation (CEE N 1107, 12 June 1996) (Romano et al., 2001).

Buffalo milk is receiving increasing research interest and investment in various countries, owing mainly to its attractive nutrient content (Amarjit and Toshihiko, 2003). It is ranked second in the world after cow's milk, being more than 12% of the world's milk production (CNIEL, 2002).

Considering the economic potential of water buffaloes, the issue of controlling parasitic infections is of great relevance because these parasitic infections can cause large health, production and economic damage (Condoleo et al., 2007, Veneziano et al., 2007).

There is worldwide trend towards the use of highly potent, broad-spectrum drugs for control of livestock parasites (Wardhaugh et al., 2001), as moxidectin and eprinomectin.

Moxidectin is a milbemycin endectocide compound active at extremely low dosages against a wide variety of nematodes and arthropod parasites. Moxidectin is widely used in domestic species of animals. It is currently marketed as a pour-on formulation (Cydectin^® pour-on) and an aqueous-based injectable formulation (Cydectin^® injectable) for cattle.

The plasma kinetic behaviour (Lanusse et al., 1997) and tissue distribution (Lifschitz et al., 1999) of moxidectin in cattle and sheep has been characterized after subcutaneous administration of the drug (Alvinerie et al., 1998). Moxidectin is much more lipophilic than ivermectin or eprinomectin and is mainly stored in fat. This appears to have an accumulatory effect and results in a long mean residence time (MRT) for the drug in the body, as it has been demonstrated in cows (Alvinerie et al., 1999b), in sheep (Alvinerie et al., 1998), in goats (Carceles et al., 2001) and in horses (Perez et al., 1999).

Eprinomectin is a member of avermectin class. It was selected after examination of several hundred analogues because it possessed the most potent broad-spectrum activity against nematodes (Shoop et al., 1996). It contains no less than 90% of the B_1a component and no more than 10% of the B_1b component. These homologues differ by only one methylene unit (–CH₂–) at the C₂₅ position, the B_1a component containing an isopropyl group. Because of its partitioning profile between plasma and milk (Alvinerie et al., 1999b), eprinomectin is the only endectocide approved for use during lactation with a zero milk-withdrawal period in cattle.

Although pharmacokinetic data from cattle have been reported, these data have not been described in water buffaloes. Due to the physiological adaptations of these species to their environment, drugs pharmacokinetics may be different in comparison with other bovine species.

Endectocides exert their effects in non-vascular tissues into which they must be distributed from the central blood compartment. There is a strong correlation between plasma concentration and target tissues (Lifschitz et al., 1999). The plasma pharmacokinetics studies of endectocides in association with efficacy studies on parasites remain the main tool to check their efficacy and avoid their misuse which led to the widespread distribution of parasite resistance. It is well recognized that drug efficacy is more precisely predicted on the basis of blood levels than dose, for systemically active compounds. The rational use of a drug requires knowledge of basic pharmacokinetic parameters and, in food animals, residue concentrations in edible tissue and withdrawal times.

The aim of this study was to determine the comparative plasma and milk pharmacokinetic parameters of eprinomectin and moxidectin in water buffaloes after a pour-on administration at the dose of 0.5 mg kg⁻¹.

Section snippets

Animals

The trial was conducted on December 2006, on a commercial buffalo farm located in the Salerno province of southern Italy. The herd consisted of approximately 200 buffaloes. The trial was performed upon a total of 10 randomly selected lactating water buffaloes, between 1 and 2 years old, and between 500 and 600 kg in body weight. They were double ear-tagged for identification and housed communally in an indoor pen until the day 0 of the trial. A total mixed ration, i.e. crude protein/dry matter

Results

The analytical method used to extract, derivatize and quantify the plasma and milk concentration of eprinomectin and moxidectin by chromatographic analysis using fluorescence detector was validated adequately.

The semi-logarithmic plot of the mean plasma and milk concentrations vs. time of moxidectin and eprinomectin after topical administration of 0.5 mg kg⁻¹ are shown in Fig. 1, Fig. 2, respectively. Moxidectin was detected from 4 h and 12 hours after administration in plasma and milk,

Discussion

The effectiveness and dosage of an endectocide depend on the formulation of the compound and on its route of administration, bioavailability, pharmacokinetics behaviour and pattern of metabolism. These factors determine the plasma concentration–time profile of the drug at the site of action. The influence of these factors varies due to differences in the chemical structure of the drugs and with the animal species. Moxidectin belongs to the milbemycin family and is the most lipophilic

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Reindeer (Rangifer tarandus tarandus) are exposed to the pathogenic parasitic nematode Elaphostrongylus rangiferi during grazing. The severity of disease is dose-dependent. Prophylactic anthelmintic treatment is needed to improve animal health and reindeer herding sustainability. Herds are traditionally only gathered once during the summer, requiring a drug with a persistent effect. In this study we investigated the suitability of long-acting eprinomectin, given as a single subcutaneous injection at 1 mg/kg bodyweight in adult reindeer and calves. Plasma and faeces concentrations were determined using ultra-high performance liquid chromatography high resolution mass spectrometry (UHPLC-HRMS). Plasma concentrations remained above the presumed effect level of 2 ng/mL for 80 days, demonstrating the drug’s potential. Pharmacokinetic parameters were compared to other species using allometric scaling. Calves and adults had slightly different profiles. No viable faecal nematode eggs were detected during treatment. Eprinomectin was measurable in the reindeer faeces up to 100 days, which is of environmental concern.
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Similar pharmacokinetic studies have been carried out in water buffalo [329] and cattle [330]. In all cases, EPM concentrations in milk were below the allowed levels for human consumption, as opposed to moxidectin (83), another semisynthetic ivermectin analog with much higher transport into milk [329]. Other antibiotics unrelated to the much exploited ivermectin and β-lactam families are also excreted through the mammary gland.
Few researchers in the phytochemical sciences regard milk as a bioactive natural product. However, milk emanates entirely from living mammals and every carbon atom in milk stems directly or indirectly from plants, fungi, and bacteria with the exception of anthropogenic contaminants. In addition to the usual constituents of milk, lactogenesis or milk synthesis drags with it a substantial number of adventitious organic compounds, healthy, and appetizing or downright harmful and repulsive, acquired through diet, breath, and skin absorption. Animals and people alike are exposed to a large number of organic pollutants, pharmaceutical drugs, substances from wood combustion for cooking and heating, and many other sources related to human activities. These nonnatural products can reach pristine remote pastures carried by long range air circulation, posing new challenges to dairy cattle husbandry. Many of these compounds are carried over to milk passing through the animal in proportion to the lipid-to-water partition coefficients and to physicochemical features well defined by their molecular structure. Several compounds uptaken in blood get across the plasma–milk barrier by way of passive diffusion or aided by specific transmembrane transporters. Milk chemistry is also a complex biochemical subject. As a most nutritious medium, milk harbors numerous bacteria, fungi, and yeasts that modify deeply its natural chemistry through catabolism of existing compounds or introducing new ones. If pathogen infestation of milk continues to be a major problem, in part due to the formation of obnoxious exo and endotoxins and other products of their metabolism, the complex microcosm thriving in milk is also a source of opportunities for the dairy industry. Proper management and deep knowledge of the natural organic chemistry of milk and downstream dairy products can not only prevent product spoilage but also enhance its nutritional, nutraceutical, and taste qualities. This latter property is extensively being exploited to manufacture cultured creams, yogurts, spreads, and cheeses of ever growing sophistication, as are methods of analytical organic chemistry and quality control of milk feedstocks. In reviewing the literature of the past 25 years and up to mid-2016, this chapter emphasizes the natural product essence of milk as a biochemically living stuff of exceedingly complex and dynamic organic chemistry, subject to great variability considering the number of inputs from the outside of the mammal, internal processing of the ingested organic materials, microbial intervention in the digestive tract in healthy and diseased livestock, and the multifarious ripening of fermented dairy products that make them favorite foods for millions of people across the world.
Selection for anthelmintic resistant Teladorsagia circumcincta in pre-weaned lambs by treating their dams with long-acting moxidectin injection
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The long persistency associated with moxidectin, (Carceles et al., 2001; Imperiale et al., 2004), and the continuous release of abamectin by the CRC mean that these actives are present in plasma and tissue in the ewe for many weeks after lambs are born. Like all ML compounds, the lipophylic nature of moxidectin and abamectin results in a proportion of the administered dose being excreted in the milk of lactating animals (Alvinerie et al., 1996; Oukessou et al., 1999; Carceles et al., 2001; Imperiale et al., 2004; Dupuy et al., 2008; Barrera et al., 2013) and being detectable in the plasma of suckling offspring (Bogan and McKellar, 1988; Alvinerie et al., 1996; Cerkvenik-Flajs et al., 2007). This raises the possibility that treatment of ewes pre-lambing with these long-acting products could result in sufficient transfer of active ingredient to the suckling lamb to result in anthelmintic activity, and the potential for subsequent selection for ML-resistant parasites in the lambs (Dever and Kahn, 2015).
Administration of long-acting anthelmintics to pregnant ewes prior to lambing is a common practice in New Zealand. Today, most of these products contain macrocyclic lactone (ML) actives, which because of their lipophilic nature, are detectable in the milk of treated animals and in the plasma of their suckling offspring. This study was conducted to confirm the transfer of ML actives to lambs in the ewe's milk, and to assess whether this could result in selection for ML resistant nematodes in the lamb. Ninety, twin bearing Romney ewes were treated before lambing with a long-acting injectable formulation of moxidectin, a 100-day controlled release capsule (CRC) containing abamectin and albendazole, or remained untreated. After lambing, seven ewes from each treatment group were selected for uniformity of lambing date and, along with their twin lambs, relocated indoors. At intervals, all ewes and lambs were bled, and samples of ewe's milk were collected, for determination of drug concentrations. Commencing 4 weeks after birth all lambs were dosed weekly with 250 infective larvae (L3) of either an ML-susceptible or –resistant isolate of Teladorsagia circumcinta. At 12 weeks of age all lambs were slaughtered and their abomasa recovered for worm counts. Moxidectin was detected in the plasma of moxidectin-treated ewes until about 50 days after treatment and in their lambs until about day 60. Abamectin was detected in the plasma of CRC-treated ewes until the last sample on day 80 and in the plasma of their lambs until about day 60. Both actives were detectable in milk of treated ewes until day 80 after treatment. Establishment of resistant L3 was not different between the treatment groups but treatment of ewes with moxidectin reduced establishment of susceptible L3 by 70%, confirming the potential of drug transfer in milk to screen for ML-resistance in the suckling lamb.
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Eprinomectin is a very broad-spectrum endectocide derived from the natural product of avermectin B1. Owing to its high efficacy for nematode control and its low milk-to-plasma concentration ratio, eprinomectin has been evaluated for treating parasite infestations in many animal species, including dairy sheep (Hodošček et al., 2008), goats (Alvinerie et al., 1999a) and water buffalo (Dupuy et al., 2008). Furthermore, eprinomectin is recommended to use in lactating and food-producing animals because of its low residue in plasma and milk (Baoliang et al., 2006).
Eprinomectin is recommended for use as an anti-parasitic agent in livestock, including cattle. Yaks are a member of the cattle family living in the high altitude mountains of China and adjacent countries; however, there have been no clinical trials of the anthelmintic efficacy and pharmacokinetics of eprinomectin in yaks. The purpose of this study was to investigate the endectocidal efficacy and pharmacokinetics of eprinomectin following topical (at 0.5 mg/kg) and subcutaneous (at 0.2 mg/kg) administration in the yak. After topical administration, plasma eprinomectin reached a peak value of 15.31 ± 3.71 ng/ml (C_max) at 3.01 ± 1.22 days (T_max). In milk, the C_max was 3.74 ± 1.05 ng/ml at 3.00 ± 0.88 days. The AUC_0-t for plasma was 193.84 ± 26.34 ng d/ml and for milk AUC_0-t was 46.24 ± 10.37 ng d/ml. The mean residence time (MRT) was 10.74 ± 1.44 days and 10.90 ± 3.87 days in plasma and milk, respectively. After subcutaneous administration, the C_max was 35.78 ± 10.53 ng/ml at 0.91 ± 0.39 days in plasma and 9.10 ± 3.61 ng/ml at 1.61 ± 1.05 days in milk. The MRTs in plasma and milk were 3.07 ± 1.50 and 3.64 ± 1.15 days, respectively. The AUC_0-t was 133.71 ± 32.51 ng d/ml for plasma and 43.85 ± 14.16 ng d/ml for milk. Both the pour-on and injectable formulation of eprinomectin were similarly efficacious (minimum egg count reductions of 94% and 96.4%, respectively) at each post-treatment time point. However, T_max, MRT and t_1/2el were longer, and C_max of eprinomectin in the plasma and milk were lower, following topical administration compared to those after subcutaneous administration. In conclusion, these results support the use of eprinomectin in yaks. The pour-on formulation of eprinomectin can be recommended for nematode control in lactating yaks with no milk-withdrawal period because of its low residue profile and good efficacy.
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This is a novel finding describing the reduction in WEC for lambs suckling TX ewes, providing evidence for the transfer of lipophilic anthelmintics via milk to the suckling lamb. Moxidectin and monepantel concentrations in milk and plasma were not analysed in this experiment but residues of both actives have been reported in milk (Carceles et al., 2001; Imperiale et al., 2004; Dupuy et al., 2008; European Medicines Agency, 2013) and moxidectin in the plasma of a calf suckling a cow treated with moxidectin (Alvinerie et al., 1996). The reduction in WEC of lambs suckling TX ewes suggests strongly that drench active/s were transferred to lambs via milk to constitute ingestion of a sub-therapeutic dose.
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With exception of flunixin, all nonantibiotic drugs including moxidectin exhibited interaction with bABCG2. Concordantly, previous PK studies reported high M/P ratios of moxidectin in dairy cows and buffalos31,41 indicating carrier-mediated drug secretion into milk. Similar drug–carrier interactions were observed for cABCG2.
The ATP-binding cassette subfamily G member 2 (ABCG2) transporter is a member of the ATP-binding cassette (ABC) family of efflux carriers that mediates cellular extrusion of various drugs and toxins. In the mammary gland, ABCG2 is expressed at the apical membrane of alveolar epithelial cells and is induced during lactation. It is well established that ABCG2 plays the main role in active secretion of xenobiotics into milk of humans and mice. In contrast, no detailed information is as yet available about functional activity and substrate spectrum of ABCG2 in dairy animals. Therefore, we cloned full-length ABCG2 from bovine, ovine and caprine lactating mammary gland tissues using rapid amplification of complementary DNA (cDNA) ends polymerase chain reaction. The generated full-length ABCG2 cDNA constructs were stably transduced in MDCKII cells. Functional ABCG2 efflux activity was demonstrated with the Hoechst H33342 accumulation assay using the specific ABCG2 inhibitor Ko143. The established ruminant MDCKII-ABCG2 cell culture models in conjunction with the H33342 transport assay showed interaction of various drugs such as cefalexin and albendazole with bABCG2, oABCG2 or cABCG2. Moreover, the flavonoids equol and quercetin exhibited interaction with all ruminant ABCG2 clones. Altogether, our generated cell culture models allowed rapid and high-throughput screening of potential ruminant ABCG2 substrates and thus increase the understanding of carrier-associated secretion of xenobiotics into milk.

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Plasma and milk kinetic of eprinomectin and moxidectin in lactating water buffaloes (Bubalus bubalis)

Abstract

Introduction

Section snippets

Animals

Results

Discussion

J. Chromatogr. B: Biomed Appl.

Res. Vet. Sci.

Res. Vet. Sci.

Res. Vet. Sci.

Vet. Parasitol.

Int. J. Food Microbiol.

Vet. J.

Int. J. Parasitol.

Vet. Parasitol.

Plasma profile study of moxidectin in a cow and its suckling calf

Vet. Res.

The pharmacokinetics of moxidectin after oral and subcutaneous administration to sheep

Vet. Res.

Some pharmacokinetic parameters of eprinomectin in goats following pour-on administration

Vet. Res. Commun.

Role of buffalo in the socioeconomic development of rural Asia: current status and future prospectus

Anim. Sci. J.