Ivermectin (IVM) is a broad-spectrum antiparasitic drug extensively used in veterinary medicine. The composition of the pharmaceutical preparation affects IVM absorption and its systemic ...availability. After the introduction of the first approved IVM formulation (propylene glycol/glycerol formal 60:40) used at 200μg/kg, different pharmaceutical modifications have been assayed to extend IVM persistent endectocide activity. Recently, IVM 3.15% long-acting (IVM-LA) preparations to be administered at 630μg/kg to cattle were introduced into the veterinary pharmaceutical market. The work reported here was designed to evaluate the comparative IVM absorption pattern and plasma concentration profiles obtained after subcutaneous administration of the classic pioneer IVM formulation (1%) and two different commercially available IVM-LA preparations (3.15%) to cattle. Twenty-eight Holstein heifers were divided in four experimental groups (n=7) and treated subcutaneously as follows—Group A: IVM 1% given at 200μg/kg, Group B: IVM 1% administered at 630μg/kg, Group C: IVM-LA (A) injected at 630μg/kg and Group D: IVM-LA (B) given at 630μg/kg. Blood samples were taken between 0.5 and 90 days post-treatment and IVM plasma concentrations were determined by HPLC with fluorescence detection. There were no differences in the persistence of IVM plasma concentrations after the administration of IVM 1% formulation at the two used dose levels (200 and 630μg/kg). Higher peak plasma concentration (Cmax) and shorter mean residence time (MRT) were obtained for IVM 1% given at 630μg/kg (Group B) compared to the treatments with both IVM-LA preparations. The IVM-LA (A) formulation showed a more extended absorption process than IVM-LA (B) preparation, which accounted for a longer persistence of detectable IVM plasma concentrations. The parasitological implications of the observed differences in peak plasma concentrations (Cmax values) and in the IVM concentration levels measured from day 20, and afterwards until day 90 post-treatment, between the different preparations assayed need to be elucidated. The characterization of the absorption patterns and kinetic behaviour obtained after injection of these novel long-acting formulations used at three times the therapeutic dose recommended for the classic IVM preparation in cattle is a further contribution to the field.
Ivermectin (IVM) and moxidectin (MXD) are broad-spectrum endectocide antiparasitic drugs extensively used in food-producing animals. The patterns of IVM and MXD excretion in milk were comparatively ...characterized following their subcutaneous administration (200 μg·kg-1 of body weight) to lactating dairy sheep. The relationship between milk excretion and plasma disposition kinetics of both compounds was characterized. A pool of milk collected from all of the animals in each experimental group was used for cheese elaboration. IVM and MXD residual concentrations were assessed during the cheese-making process and ripening period. IVM and MXD concentrations were measured in plasma, milk, and milk product (whey, curd, and cheese) samples using an HPLC-based methodology with fluorescense detection. IVM and MXD were extensively distributed from the bloodstream to the mammary gland, and large quantities, particularly of MXD, were excreted in milk. Residual concentrations of both compounds were recovered in milk up to 30 (IVM) and 35 (MXD) days post-treatment. The total fraction of the administered dose excreted in milk for MXD was significantly higher than that of IVM. During cheese production, the highest residual concentrations of both molecules were measured in the curd. Thirty-four percent of the total drug residue measured in the pooled milk collected from treated sheep was lost during the cheese-making process. The lowest residual concentrations were measured in the whey. IVM and MXD concentrations in the elaborated cheese tended to increase during the ripening period, reaching the highest residual level at 40 days of cheese maturation. The long persistence of milk residual concentrations of MXD and IVM in lactating dairy sheep and the high concentrations found in cheese and other milk-related products should be seriously considered before recommendation of the extralabel use of these antiparasitic drugs in dairy animals. Keywords: Endectocide drugs; ivermectin; moxidectin; milk residues; cheese; curd; whey; dairy sheep
Closantel (CLS) is currently used in programs for the strategic control of gastrointestinal nematodes. CLS is extralabel used in different dairy goat production systems. From available data in dairy ...cows, it can be concluded that residues of CLS persist in milk. The current work evaluated the concentration profiles of CLS in plasma and milk from lactating orally treated dairy goats to assess the residues pattern in dairy products such as cheese and ricotta. Six (6) female Saanen dairy goats were treated orally with CLS administered at 10 mg/kg. Blood and milk samples were collected between 0 and 36 days post‐treatment. The whole milk production was collected at 1, 4, 7, and 10 days post‐treatment to produce soft cheese and ricotta. CLS concentrations in plasma, milk, cheese, whey, and ricotta were determined by HPLC. The concentrations of CLS measured in plasma were higher than those measured in milk at all sampling times. However, the calculated withdrawal time for CLS in milk was between 39 and 43 days postadministration to dairy goats. CLS residual concentrations in cheese (between 0.93 and 1.8 μg/g) were higher than those measured in the milk used for its production. CLS concentrations in ricotta were sixfold higher than those in the milk and 20‐fold higher than those in the whey used for its production. The persistent and high residual concentrations of CLS in the milk and in the cheese and ricotta should be seriously considered before issuing any recommendation on the extralabel use of CLS in dairy goat farms.
The pattern of in vivo uptake of albendazole (ABZ) and its major metabolite, ABZ-sulphoxide (ABZSO), by
Haemonchus contortus and
Fasciola hepatica recovered from ABZ-treated sheep, was investigated. ...Concentration profiles of both compounds were simultaneously measured in target tissues/fluids from the same infected sheep. In addition, the proportion of the (+) and (−) ABZSO enantiomers was determined in plasma, bile and
F. hepatica recovered from treated sheep. Sheep naturally infected with
H. contortus were intraruminally (i.r.) treated with ABZ (micronized suspension, 7.5
mg/kg) and the plasma concentrations of ABZSO and ABZ-sulphone (ABZSO
2) determined in addition to the concentration of ABZ and ABZSO in
H. contortus, abomasal mucosa and fluid content samples. In addition,
F. hepatica artificially infected sheep were treated i.r. with the same ABZ suspension (7.5
mg/kg), and samples of blood, bile, liver tissue and adult flukes were collected and analysed by HPLC to determine the concentrations of ABZ and both enantiomers of ABZSO. ABZSO and ABZSO
2 were the analytes recovered in plasma with ABZ and ABZSO present in
H. contortus. ABZ was the analyte recovered at the highest concentration in
H. contortus and abomasal mucosa, whereas higher concentrations of ABZSO were measured in abomasal fluid content. Only low concentrations of ABZ were detected in
F. hepatica and bile, but markedly higher concentrations of ABZ were measured in liver tissue. ABZSO was the main molecule recovered in
F. hepatica, plasma and bile samples collected from ABZ-treated sheep. The (+) enantiomer of ABZSO was recovered at a higher proportion in plasma (75%), bile (78%) and
F. hepatica (74%) after ABZ administration to infected sheep.
The role of the drug efflux pump, known as P-glycoprotein, in the pharmacokinetic disposition (host) and resistance mechanisms (target parasites) of the macrocyclic lactone (ML) antiparasitic ...compounds has been demonstrated. To achieve a deeper comprehension on the relationship between their pharmacokinetic and pharmacodynamic behaviors, the aim of the current work was to assess the comparative effect of loperamide, a well-established P-glycoprotein modulator, on the ivermectin and moxidectin disposition kinetics and efficacy against resistant nematodes in cattle. Fifty (50) Aberdeen Angus male calves were divided into five (5) experimental groups. Group A remained as an untreated control. Animals in the other experimental Groups received ivermectin (Group B) and moxidectin (Group C) (200
μg/kg, subcutaneuosly) given alone or co-administered with loperamide (0.4
mg/kg, three times every 24
h) (Groups D and E). Blood samples were collected over 30
days post-treatment and drug plasma concentrations were measured by HPLC with fluorescence detection. Estimation of the anthelmintic efficacy for the different drug treatments was performed by the faecal egg count reduction test (FECRT). Nematode larvae were identified by pooled faecal cultures for each experimental group.
Cooperia spp. and
Ostertagia spp. were the largely predominant nematode larvae in pre-treatment cultures. A low nematodicidal efficacy (measured by the FECRT) was observed for both ivermectin (23%) and moxidectin (69%) in cattle, which agrees with a high degree of resistance to both molecules.
Cooperia spp. was the most abundant nematode species recovered after the different drug treatments. The egg output reduction values increased from 23% to 50% (ivermectin) and from 69% to 87% (moxidectin) following their co-administration with loperamide. Enhanced systemic concentrations and an altered disposition of both ML in cattle, which correlates with a tendency to increased anthelmintic efficacy, were observed in the presence of loperamide. Overall, the
in vivo modulation of P-glycoprotein activity modified the kinetic behavior and improved the efficacy of the ML against resistant nematodes in cattle. The work provides further evidence on the high degree of resistance to ML in cattle nematodes and, shows for the first time under field conditions, that modulation of P-glycoprotein may be a valid pharmacological approach to improve the activity and extend the lifespan of these antiparasitic molecules.
The current experimental work reports on the comparison of the milk residue profile of the benzimidazole (BZD) anthelmintics after their administration by the oral and subcutaneous (SC) routes to ...dairy cows. The cows were distributed in four groups and treated as follows—Group 1: oxfendazole (OFZ) by oral route (5
mg
kg
−1); Group 2: albendazole (ABZ) by oral route (5
mg
kg
−1); Group 3: albendazole sulphoxide (ABZSO) by SC administration (3
mg
kg
−1); Group 4: OFZ by SC route (3
mg
kg
−1). After drug administrations milk samples were collected and frozen at −20
°C until analyzed by liquid chromatography (LC). A complete validation of the analytical methodology was accomplished. Regression curves were linear over the concentrations examined and the correlation coefficients (
r) ranged between 0.994 and 0.999. The mean extraction recovery range between 77 and 97%. Residual concentrations of OFZ, fenbendazole sulphone (FBZSO
2) and FBZ were recovered in milk after OFZ oral administration. OFZ reached the highest concentration in milk (0.39
±
0.10
μg
ml
−1) at 12
h post-treatment, being detected up to 72
h post-treatment. In contrast, FBZ was not detected in cow milk and FBZSO
2 was the main analyte recovered from the milk with the maximum milk residues (0.042
±
0.003
μg
ml
−1) achieved at after 36
h following the SC injection of OFZ. ABZSO and ABZSO
2 were the metabolites recovered in milk following oral (ABZ) and SC (ABZSO) treatments in dairy cows. ABZSO
2 was the analyte recovered at the highest residual concentration (0.86
±
0.33
μg
ml
−1) at 12
h after oral administration of ABZ. However, ABZSO was the main compound measured in cow milk following its SC injection (0.18
μg
ml
−1) at 12
h post-treatment. Overall, the total milk residue levels (sum of parent drug and metabolites) were higher after oral compared to parenteral treatments in dairy cows. These results reported here are discussed according to the acceptable maximum residue limits (MRLs) established for BZD compounds in cow milk.
Pharmacokinetic studies have been used traditionally to characterize drug concentration profiles achieved in the bloodstream. However, endectocide molecules exert their persistent and broad spectrum ...activity against parasites localized in many different tissues. The aim of this study was to compare the distribution of ivermectin (IVM) and doramectin (DRM) to different tissues in which parasites are found following subcutaneous administration to calves. Holstein calves weighing 120–140
kg were injected in the shoulder area with commercially available formulations of IVM (Ivomec 1% MSD AGVET, NJ, USA) (Group A) or DRM (Dectomax 1%, Pfizer, NY, USA) (Group B). Two treated calves were sacrificed at 1, 4, 8, 18, 28, 38, 48 or 58 days post-treatment. Plasma, abomasal and small intestinal fluids and mucosal tissues, bile, faeces, lung and skin samples were collected, extracted, derivatized and analyzed by high performance liquid chromatography (HPLC) with fluorescence detection to determine IVM and DRM concentrations. IVM and DRM were distributed to all the tissues and fluids analyzed. Concentrations >0.1
ng/ml (ng/g) were detected between 1 and 48 days post-treatment in all the tissues and fluids investigated. At 58 days post-treatment, IVM and DRM were detected only in bile and faeces, where large concentrations were excreted. Delayed
T
max values for DRM (4 days post-administration) compared to those for IVM (1 day) were observed in the different tissues and fluids. High IVM and DRM concentrations were measured in the most important target tissues, including skin. The highest IVM and DRM concentrations were measured in abomasal mucosa and lung tissue. Enhanced availabilities of both IVM (between 45 and 244%) and DRM (20–147%) were obtained in tissues compared to plasma. There was good correlation between concentration profiles of both compounds in plasma and target tissues (mucosal tissue, skin, and lung). Drug concentrations in target tissues remained above 1
ng/g for either 18 (IVM) or 38 (DRM) days post-treatment. The characterization of tissue distribution patterns contributes to our understanding of the basis for the broad-spectrum endectocide activity of avermectin-type compounds.
Sallovitz, J. M., Nejamkin, P., Lifschitz, A. L., Virkel, G. L., Imperiale, F. A., Lanusse, C. E. Comparative in vitro characterization of moxidectin and doramectin percutaneous absorption through ...bovine skin. J. vet. Pharmacol. Therap. 35, 184–192. Topical formulations have achieved worldwide acceptance in veterinary medicine because their administration is an easy, less labor‐intensive and nonstressing form. Any chemical compound that comes in contact with the skin has the potential to be locally and/or systemically absorbed. However, many factors related to the features of animal skin, composition of the topical formulation and to the drug itself can determine marked differences in the percutaneous absorption process. The aim of the current work was to characterize the pattern of in vitro percutaneous absorption for moxidectin (MXD) and doramectin (DRM), two of the most worldwide used topical macrocyclic lactone antiparasitic compounds in cattle. The work included the development of a simple and inexpensive in vitro assay useful to predict in vivo drug percutaneous absorption in cattle. Both drugs were administered as the commercial formulations intended for their topical administration to cattle. The in vitro studies were carried out using modified Franz‐type vertical diffusion cells. Cattle skin slices of 500 μm thickness were prepared using a dermatome to separate the stratum corneum and upper epidermis from dermis and subcutaneous tissue. The receptor medium was sampled up to 72 h postadministration and drug concentrations were measured by HPLC. The parameters used to estimate the comparative in vitro skin permeation showed marked differences between DRM and MXD. A 5.29‐fold longer lag time (Tlag) was observed for DRM. Similarly, the flux (J) (2.93‐fold) and the permeation coefficients (Kp) (2.95‐fold) in cattle skin were significantly higher (P < 0.05) for DRM compared to those obtained for MXD. Additionally, the data obtained from the in vitro permeation studies was correlated with the plasma concentrations of both compounds achieved in vivo in cattle treated with the same topical formulations. Correlation coefficients between percentage of drug permeated in vitro vs. percentage of drug absorbed in vivo (up to 48 h post‐treatment) were 0.856–0.887 (MXD) and 0.976–0.990 (DRM). However, the highest in vitro–in vivo correlations for both molecules were observed up to 24 h post‐treatment A rapid screening method for testing different topical formulations can be achieved with the simple in vitro cattle skin permeation technique described here, which has been successfully adapted to test the comparative percutaneous absorption of MXD and DRM.
The pharmacokinetic profile of avermectin and milbemycin compounds is affected by different drug- and host-related factors. This work reports the influence of cattle breeds on the plasma kinetics of ...moxidectin (MXD) after topical (pour-on) administration. Parasite-free Aberdeen Angus and Holstein calves were treated with a commercial MXD pour-on formulation at 500
μg/kg. Blood samples were collected over a period of 35 days post-treatment and the recovered plasma was analysed by high performance liquid chromatography using fluorescence detection. MXD was detected in plasma from two hours up to 35 days post-treatment in animals from both breeds. A slow MXD absorption and delayed peak plasma concentration were observed in Aberdeen Angus compared to Holstein calves. Significant lower systemic availability (expressed as AUC) (
P<0.01) and peak plasma concentration (C
max) (
P<0.05) were also observed in Aberdeen Angus calves, although the plasma mean residence time (MRT) and elimination half-lives (T
1/2el) of MXD in both breeds were similar. The pharmacokinetic differences observed between cattle breeds contribute to explain the variability in the pattern of clinical efficacy for pour-on administered endectocide compounds reported in different field trials.
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