Pharmacokinetics of Anthelmintics in Animals

As a chemical class, the benzimidazoles have only limited water solubility, which mainly restricts their preparation to suspensions for oral or intraruminal administration (see figure Levamisole and albendazole comparison).

Drug particles must dissolve in enteric fluids to facilitate absorption of the benzimidazole molecule through the GI mucosa. Benzimidazole dissolution is notably increased by extreme pH values. In ruminants, dissolution occurs mainly in the abomasum due to its low pH. Drugs that do not dissolve in the GI contents pass down and are excreted in the feces without exerting their action.

Shortly after administration, benzimidazole compounds are almost completely adsorbed to the digesta particulate material, reaching equilibrium between the particulate and fluid portions of the digesta. The rumen acts as a drug reservoir by slowing digesta transit time, which results in improved systemic availability of benzimidazole compounds because of greater drug particle dissolution in the acid pH of the abomasum. Plasma levels of the parent sulphides (ie, albendazole, fenbendazole) and/or their active sulfoxide metabolites (albendazole sulfoxide, oxfendazole) reflect the amount of drug dissolved at the GI level.

For oral anthelmintics, first-pass metabolism (ie, biotransformation) affects the drugs' systemic exposure and, therefore, the amount of active drug that reaches the GI tract and other tissues of parasite location. Biotransformation takes place predominantly in the liver, although there is also metabolic activity is apparent in extrahepatic tissues, eg, by ruminal and intestinal microflora. For example, the high efficacy of albendazole sulfoxide and oxfendazole against GI-located nematodes may depend, in part, on this bacterial reduction of the sulfoxide to more pharmacologically active thioethers. In fact, although albendazole is not detected in the bloodstream, it is found in high concentration in abomasal mucosa as well as within Haemonchus contortus recovered from treated sheep. The extensive distribution of benzimidazole methylcarbamates from the bloodstream to the GI tract and other tissues may contribute to good anthelmintic efficacy against parasites localized in body tissues, including GI mucosa, GI lumen, and lungs.

A number of benzimidazole compounds (eg, febantel, thiophanate, netobimin) exist in the form of prodrugs (pro-benzimidazoles) that must be metabolized in the body to the biologically active benzimidazole carbamate nucleus. Febantel is hydrolyzed to the active metabolite fenbendazole, and netobimin undergoes processes of reduction, cyclization, and oxidation to yield albendazole sulfoxide.

Compromised drug availability in the bloodstream and target tissues, resulting in a subtherapeutic exposure of those individuals carrying resistant alleles, may facilitate progressive development of resistance.

Several host-related factors can affect the kinetics and resultant efficacy of benzimidazole in production animals. Absorption and biotransformation are two of the most important processes affected by those factors. Manipulation of the pharmacokinetic/metabolic patterns and the comprehension of factors modulating them are excellent strategies to improve benzimidazole use in ruminants.

Modified feeding management has been recommended to restore anthelmintic activity of compounds whose potency has been compromised by resistance. Enhanced plasma availability of oxfendazole induced by temporary feed restriction in sheep accounted for the drug's increased efficacy against benzimidazole-resistant nematode strains. The reported fasting-induced changes to the kinetic behavior and quantitative tissue distribution of albendazole and albendazole sulfoxide in cattle have been particularly relevant strategies to increase activity against susceptible parasites and to delay development of resistance strains. The increased concentration of active drug measured in tissues (ie, GI mucosa, lungs) where target parasites are located is a strong scientific argument to recommend the fasting approach to improve parasite control in cattle. Other, mainly pharmacotechnical, strategies have been investigated to overcome limited GI dissolution and absorption of benzimidazoles.

The rate of levamisole absorption differs with the route of administration (see figure Levamisole and albendazole comparison and see table Delivery Routes for Anthelmintics). In cattle, blood levamisole concentration peaks < 1 hour after SC administration. Systemic availability of levamisole in sheep is substantially lower after PO or intraruminal administration (42-45%) compared with after SC injection.

Levamisole is rapidly and extensively metabolized to a large number of metabolites in the liver. The main metabolizing pathways appear to be oxidation, hydrolysis, and hydroxylation. Excretion of levamisole and metabolites (glucuronyl or S-cysteinyl-glycine conjugates) occurs via urine (60%) and feces (30%). Because levamisole is short-lived in plasma and GI contents, peak concentration, rather than duration of exposure, is important for its anthelmintic effect.

Levamisole use as a nematicidal compound in domestic animal species decreased after the introduction of safe broad-spectrum anthelmintics, such as benzimidazole methylcarbamates (albendazole, fenbendazole, etc) and macrocyclic lactones. However, levamisole remains a useful nematicidal compound as a result of an acceptable margin of safety and spectrum of activity along with very low cost. Its worldwide use as a nematicidal compound markedly increased when widespread development of drug resistance to other chemical families (ie, benzimidazoles and macrocyclic lactones) became a serious threat for nematode control in production animals.

Pyrantel and its methyl analogue morantel are the two members of the tetrahydropyrimidine family available in the veterinary market. Pyrantel is formulated as tartrate, citrate, or pamoate (also known as embonate) salts. Morantel is mainly formulated as a tartrate salt.

Pyrantel tartrate (or citrate) is well absorbed by pigs and dogs but less well by ruminants. The pamoate salt (embonate) of pyrantel is poorly soluble in water; this offers the advantage of decreased absorption from the gut and allows the drug to be effective against parasites in the large intestine, which makes it useful in horses and dogs.

Morantel is negligibly absorbed in cattle and therefore is largely excreted as the unmetabolized parent compound in feces. Low GI absorption and/or efficient metabolism to inactive metabolites explains the absence of systemic anthelmintic activity against lungworms as well as the arrested tissue larvae.

Metabolism of pyrantel is rapid, and metabolites are excreted rapidly in urine (40% of the dose in dogs); some unchanged drug is excreted in feces (principally in ruminants). Blood levels usually peak 4–6 hours after PO administration.

Avermectins and milbemycins are closely related macrocyclic lactones, produced through fermentation by soil-dwelling actinomycetes (Streptomyces spp). The families share some structural and physicochemical properties as well as broad-spectrum antiparasitic activity against nematodes and arthropods at extremely low doses.

• The avermectin family includes a series of natural and semisynthetic molecules (eg, abamectin, ivermectin, doramectin, and eprinomectin).

• The milbemycin family includes nemadectin, moxidectin, and milbemycin 5-oxime.

Ivermectin, doramectin, eprinomectin, and moxidectin, currently marketed as injectable, pour-on (cattle), and oral (sheep, goats, cattle, horses, pigs) formulations, are the macrocyclic lactones most commonly used worldwide to control endo- and ectoparasites in production animals (see table Delivery Routes for Anthelmintics). High lipophilicity and prolonged persistence of potent broad-spectrum activity are distinctive features of these macrocyclic lactone antiparasitic drugs.

Clinical efficacy of macrocyclic lactones is closely related to the time of parasite exposure to active drug concentrations (see figure Macrocyclic lactones: mechanisms of action).

Antiparasitic spectrum and efficacy patterns are similar among macrocyclic lactones; however, each compound has its own dosage-limiting species. Differences in physicochemical properties may account for differences in formulation flexibility, kinetic behavior, and potency and persistence of endectocide activity. Thus, even slight modifications to disposition kinetics or pattern of plasma/tissue exchange can dramatically affect persistence of the drugs' antiparasitic effect.

Factors such as animal species, level of feed intake, nutritional status/body composition, drug formulation, and route of administration have been shown to substantially affect systemic availability of different macrocyclic lactones in sheep and cattle. Macrocyclic lactones generally have poor solubility in water, but moxidectin solubility is greater than that of ivermectin and doramectin. Aqueous solubility of an active ingredient and pharmacotechnical preparation can influence its systemic availability.

Plasma profiles of ivermectin and doramectin in cattle are substantially affected by composition of the administered formulation. After SC administration to cattle, the low solubility of ivermectin and doramectin in water and their deposition in SC tissue favor slow absorption from the injection site and provide prolonged duration in the bloodstream. The rate of absorption from the SC space appears to be the rate-limiting step in the disposition of ivermectin and doramectin. The oil-based formulation of doramectin, and perhaps a slowed metabolic rate based on the presence of the cyclohexyl group at C25, may contribute to the drug's higher plasma availability compared with ivermectin and moxidectin after SC treatment.

Plasma concentration profiles may help predict the persistence of antiparasitic activity. However, measurement of drug concentration profiles at the site of parasite location permits a more direct interpretation and provides a basis for understanding the differences in therapeutic and preventive efficacies observed for macrocyclic lactones.

The characterization of drug concentrations at the sites of parasite infection for moxidectin, ivermectin, and doramectin in cattle, along with the characterization of the kinetic disposition of doramectin in fluid and particulate digesta throughout the GI tract in sheep, represented a considerable contribution to understanding the comparative persistence of activity of these compounds. Highly lipophilic macrocyclic lactones are extensively distributed from the bloodstream to different tissues. Their extensive tissue distribution agrees with the high availability of these drugs in different parasite location tissues, such as the GI mucosal tissues, lungs, and skin in cattle, where concentrations much greater than those observed in plasma were measured 50–60 days after treatment.

In several studies, researchers have compared the disposition of macrocyclic lactones in different species. Lower systemic availability of moxidectin (PO treatment) and ivermectin (SC treatment) observed in goats compared with sheep emerges as a curious finding. The influence of route of administration on macrocyclic lactone plasma availability has been investigated in sheep and cattle. Macrocyclic lactones have historically been administered by SC injection to cattle. However, formulations for their topical administration (pour-on) are marketed worldwide. Some practical advantages of the topical compared with other routes of administration have accounted for its great acceptance for parasite control in cattle.

The plasma and tissue disposition kinetics of moxidectin administered as a pour-on to cattle have been characterized. Low plasma concentrations of moxidectin were detected in cattle from 2 hours to 35 days after its pour-on administration. The absorption rate of topically administered moxidectin and its plasma availability were substantially higher in Holstein compared with Aberdeen-Angus calves, which may have considerable practical implications in terms of drug activity and persistence. Topically administered moxidectin is extensively distributed to different target tissues, including GI mucosa, lungs, and dermal layers.

Plasma and fecal disposition of ivermectin topically administered to cattle are markedly influenced by the natural licking behavior of treated animals. Higher and more variable systemic availability of ivermectin was observed in cattle that were allowed to lick, with 70% of the dose recovered in feces, compared with animals whose licking behavior was prevented (1). These results suggest natural licking behavior may have a major influence on the kinetics of macrocyclic lactones administered as a pour-on. These findings are consistent with the high moxidectin and doramectin concentrations recovered in the GI fluids of topically treated calves. There is clear evidence that the natural grooming behavior of cattle influences absorption and kinetic disposition of transdermally administered macrocyclic lactones, accounting for highly variable kinetic behavior. Overall, animal licking behavior and the well-described erratic percutaneous absorption pattern may drastically play against a successful anthelmintic therapeutic response.  

Although some metabolic products have been recovered in plasma after their administration to cattle, macrocyclic lactones are minimally metabolized in sheep and cattle, and large amounts of unchanged endectocide compounds are excreted in bile and feces. Considerable drug excretion occurs via the mammary gland, which invalidates macrocyclic lactones' use in dairy animals. Because long milk withdrawal times may be required, extralabel use of these compounds should be avoided in dairy animal species producing milk intended for human consumption.

In an effort to identify a macrocyclic lactone molecule that could be used in dairy cattle, eprinomectin was introduced and developed for topical administration to cattle. Whereas the milk:plasma ratio for ivermectin and moxidectin is close to 1:1 in sheep, goats, and cattle, the milk:plasma partitioning for eprinomectin in topically treated cattle falls between 1:10 and 1:5. These results indicate that eprinomectin has a much lower distribution to milk than do the other macrocyclic lactones. Additionally, a topical moxidectin formulation with zero withdrawal time for milk has been approved for cattle.

The extent to which the biliary-secreted drug and metabolites are presented to the gut lumen, reabsorbed as free compounds, and processed in the enterohepatic cycle is a major contributor to parasite exposure. P-glycoprotein (P-gp) is a transport protein that acts as a multidrug efflux pump, decreasing intracellular concentration of different drugs. Several anthelmintic drugs interact with P-gp. The macrocyclic lactones (eg, abamectin, ivermectin, and moxidectin) have been shown to be P-gp substrates. In mammalian hosts, P-gp participates in the mechanism of active biliary and intestinal secretion of different molecules from the bloodstream to the GI tract. Different pharmacological approaches to delay bile and intestinal secretions and to extend plasma-intestine recycling time of macrocyclic lactones have been investigated as tools to improve efficacy against resistant nematodes in sheep and cattle.

After oral administration, the amino-acetonitrile derivative monepantel is quickly absorbed into the bloodstream and rapidly converted in the liver into different metabolites. The systemic availability of the monepantel parent compound is significantly lower than that observed for its main metabolite, monepantel sulfone, which is anthelmintically active.

The characterization of monepantel and monepantel sulfone concentration profiles attained at specific GI sites and the establishment of the relationship between their plasma and tissue availabilities are relevant to understanding their antiparasitic action. The high availability of monepantel and monepantel sulfone in abomasal contents could facilitate accumulation of both active molecules within the parasite through a transcuticular diffusion process.

Emodepside is a semisynthetic derivative of PF1022A that contains a morpholine molecule attached in a para position at both D-phenyllactic acids. This novel anthelmintic molecule is efficacious against a variety of GI nematodes.

Studies in rats were performed to assess the general distribution, metabolism, and excretion patterns of emodepside after PO and IV administration. Bioavailability after PO administration is approximately 50%. Emodepside is distributed throughout the whole organism, but highest concentrations are found in fat tissues, where it forms a deposit that is slowly released. Emodepside is excreted predominantly via bile and then eliminated in feces. Approximately half the administered dose is excreted within the first 24 hours.

The elimination half-life of emodepside after both PO and IV administration is 39–51 hours. Approximately 45–56% of the administered dose is excreted unchanged, with the rest as inactive metabolites. After topical administration in cats, emodepside is absorbed slowly into the bloodstream. Maximum plasma levels are reached 2–3 days after treatment. Absorption after oral administration in dogs is higher if they have been fed first.

Derquantel is well absorbed and extensively distributed into tissues after PO administration, showing excellent anthelmintic activity against H contortus (adult stages), Trichostrongylus colubriformis, and Nematodirus spp (adults and fourth-stage larvae [L4]) in sheep.

Derquantel is lipophilic, with a large distribution volume and peak plasma concentration at 4 hours after administration to sheep. Hepatic biotransformation occurs rapidly, and elimination half-life is 9.3 hours. Derquantel is most commonly administered in combination with abamectin to improve its anthelmintic spectrum. 

The nitrophenolic compound nitroxynil is a trematocidal compound, which also holds activity against the abomasal nematode H contortus. Nitroxynil is highly effective against adult stages of Fasciola hepatica (from 8 weeks postinfection) and F gigantica. The drug is most often administered SC, as a 25% or 34% solution of nitroxynil-N-alkylglucamine. 

Formulations containing nitroxynil in combination with ivermectin and/or clorsulon are also available for ruminants and are administered SC. Though plasma concentrations in sheep are high for 3 days after treatment and can last up to 60 days, the high level of protein binding exhibited by this drug limits its tissue distribution. It may not, therefore, reach therapeutic levels against immature liver flukes.

Closantel, like nitroxynil, can be administered PO or parenterally; however, bioavailability is superior after parenteral dosing. As a consequence of its high protein binding, duration of therapeutic levels of closantel in plasma is prolonged. Thus, a single dose of closantel protects sheep against susceptible H contortus reinfection for up to 28 days.

Because the target helminths, F hepatica and H contortus, consume the host’s blood, the sustained plasma concentration of closantel confers a considerable therapeutic advantage on this drug. Closantel undergoes minimal metabolism and is eliminated in feces.

Rafoxanide (a salicylanilide) is administered PO and is well absorbed from the small intestine, particularly in nursing lambs. Like closantel, it is extensively protein bound and, as a result, exerts a prolonged effect against hepatobiliary flukes of ruminants.

Rafoxanide (12.5%) is available in combination with ivermectin (1%) as an injectable product for ruminants and camels. It is not metabolized before excretion. Rafoxanide is not permitted for use in dairy animals. Slaughter withdrawal periods should be followed per product labeling.

Praziquantel can be formulated as a tablet, paste, or suspension for PO administration and as a solution for SC or IM injections. Commercial formulations are composed of equal parts of both praziquantel enantiomers. Praziquantel's pharmacokinetic behavior and metabolic fate have been investigated in sheep and dogs. In sheep, praziquantel C_max and AUC (area under the concentration-time curve) values administered IM were 6-fold higher compared with those values observed after oral treatment at a 2-fold higher dosage.

Praziquantel is completely absorbed in the GI tract in almost all species studied. Thus, its low oral bioavailability in sheep and water buffalo is not attributed to poor GI absorption; rather, an extensive hepatic first-pass effect accounts for its decreased systemic availability. Praziquantel is secreted in bile.

• Lanusse CE, Alvarez LI, Lifschitz AL. Gaining insights into the pharmacology of anthelmintics using Haemonchus contortus as a model nematode. Adv Parasitol. 2016;93:465-518.

• Riviere JE, Papich MG, eds. Veterinary Pharmacology and Therapeutics, 10th ed. Wiley-Blackwell; 2017.

1. Laffont CM, Alvinerie M, Bousquet-Melou A, Toutain P-L. Licking behaviour and environmental contamination arising from pour-on ivermectin for cattle. Int J Parasitol.31(14):1687-1692. doi:10.1016/S0020-7519(01)00285-5