Milk Excretion of Ivermectin and Moxidectin in Dairy Sheep:  Assessment of Drug Residues during Cheese Elaboration and Ripening Period

Abstract

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 microg.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 fluorescence 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.

Overview of anthelmintic resistance of gastrointestinal nematodes of small ruminants in Brazil

“…However, there have been reports of resistance to monepantel (SCOTT et al, 2013;MEDEROS et al, 2014a; VAN DEN BROM et al, 2015) and to derquantel (KAMINSKY et al, 2011), indicating the high vulnerability of these drugs. Additional to the loss of effectiveness there are the effects of toxic residues on nontarget organisms in the environment (LUMARET et al, 2012) and of residues in meat (COOPER et al, 2011), milk and other animal products associated to anthelmintics (IMPERIALE et al, 2004;ANASTASIO et al, 2005;WHELAN et al, 2010).…”

Effect of Moxidectin Treatment at Peripartum on Gastrointestinal Parasite Infections in Ewes Raised under Tropical Andes High Altitude Conditions

“…It is possible that delayed egg excretion in lambs born from treated ewes was due to prolonged Mox secretion by milk suckling. Imperiale et al [ 46 ] showed that residual concentrations of Mox were recovered in milk up to 35 days after treatment (between 17.8 and 183.5 ng mL −1 daily). Considering that daily milk intake ranges from 1000 to 2000 mL in lambs, milk secretion of 100 ng mL −1 Mox per day would lead to ingestion of 100–200 μ g Mox per lamb per day.…”

Interaction of Macrocyclic Lactones with the Multidrug Transporters: The Bases of the Pharmacokinetics of Lipid-Like Drugs

“…When compared with ivermectin, moxidectin is characterized by a larger volume of distribution and a longer mean residence time in the host organism [23,25], that results in an interesting duration of efficacy of several weeks [21]. Moxidectin also has a higher elimination rate in the milk than ivermectin [26]. By contrast, eprinomectin shows a shorter residence time and a lower excretion rate in milk [27,28].…”

“…Ivermectin, with intermediate lipophilicity and affinity for P-gp also has an intermediate persistence in the organism ( Table 2). Also, moxidectin is more extensively eliminated in milk (containing "lipid droplets") when compared with ivermectin [26] and eprinomectin [26][27][28]. The role of P-gp has never been discussed in the context of drug secretion or reabsorption at the level of the mammary gland, and it is likely that other ABC transporters, such as BCRP, are at least partly involved.…”