ReviewThe pharmacokinetics and metabolism of ivermectin in domestic animal species
Introduction
The rational use of a drug requires knowledge of its basic pharmacokinetics in the target animal species, and this helps to optimise clinical efficacy. Ivermectin is probably one of the most widely used antiparasitic drugs worldwide, and its efficacy is well established. However, the pharmacokinetic parameters of ivermectin vary extensively and in accordance with many factors that can all influence the drug’s plasma concentration. These factors, which include the species, route of administration, vehicle used in the commercial formulation, bodyweight, body condition, physiological status, and amount and type of nutrition, create difficulties when extrapolating data from one species to another and should be considered in clinical practice in order to achieve effective levels that will last as long as possible.
Ivermectin is a mixture of two chemically modified avermectins that contain at least 80% of 22,23-dihydroavermectin-B1a and >20% 22,23-dihydroavermectin-B1b (Fig. 1). It is a highly lipophilic substance that dissolves in most organic solvents, but is practically insoluble in water (0.0004% m/v). Ivermectin was first marketed in 1981 by Merck Sharp and Dohme as an antiparasitic agent (Steel, 1993), and it remains the leading worldwide antiparasitic agent for livestock. It has exceptional potency against endo- and ectoparasites at extremely low doses (doses recommended are expressed as μg/kg); this accounts for its large margin of safety.
Ivermectin is highly active against a wide spectrum of nematode species, including most larvae and adult forms; it is also highly effective against many arthropod parasites of domestic animals (Table 1). All important gastrointestinal and lung nematodes are susceptible to the drug, including sensitive mites, ticks, biting flies, and parasitic dipteran larvae (Campbell and Benz, 1984, Campbell, 1989, McKellar and Benchaoui, 1996). In dogs, ivermectin is also active against developing larvae of Dirofilaria immitis and is used in heartworm prophylaxis.
Toxicity to ivermectin is rare across animal species. The signs of toxicosis are mydriasis and depression, followed by ataxia, recumbency, and death. It has no adverse effects on breeding performance. Some Collie dogs and other herding breeds are remarkably susceptible, but even these animals will tolerate doses of 50 μg/kg, which are nearly 10-fold greater than the therapeutic dose in dogs. The central nervous system side-effects in sensitive Collie dogs have been linked to the absence or functional deficiency of P-glycoprotein, which functions as a transmembrane efflux pump and plays a central role in limiting drug uptake by the brain, thereby protecting against ivermectin neurotoxicity.
Many rumino-reticular delivery systems, as well as oral, topical, and injectable formulations of ivermectin, are currently available at the dosage recommended by manufacturers, namely, 200 μg/kg in ruminants (500 μg/kg for topical application) and equines, 300 μg/kg in pigs, and 6 μg/kg in dogs. This paper reviews the most important aspects of ivermectin pharmacokinetics, including absorption, distribution, metabolism, and excretion (Fig. 2).
Section snippets
General overview of ivermectin pharmacokinetics and metabolism
Since its introduction in 1981, there have been numerous pharmacokinetic studies of ivermectin. The drug can be administered by oral, intramuscular (IM), subcutaneous (SC), or topical routes, depending on the species. The pharmacokinetic properties are dose-dependent, with a linear increase in the area under the curve (AUC) with increasing dose.
The route of administration and the formulation strongly affect ivermectin’s pharmacokinetics. The greatest bioavailability is achieved with the SC
Cattle
Table 3 summarises the pharmacokinetic parameters calculated for different routes of administration in cattle. SC administration is the most studied, and the results show a high degree of variability, which may be due to differences in breed, body condition, number of samples or data points, methods of quantification, and kinetic treatment of the data, or to erratic absorption from the injection site.
Despite this variability, Campbell and Benz, 1984, Benz et al., 1989 showed that the plasma
Conclusions
Although the efficacy of ivermectin has been established across a variety of domestic species, its pharmacokinetic properties differ between them, and the factors responsible for modifying ivermectin’s pharmacokinetics should be taken into account to ensure its clinical efficacy, prevent subtherapeutic levels, and minimise the development of resistance.
References (60)
- et al.
Macrocyclic lactones: distribution in plasma lipoproteins of several animal species including humans
Comparative Biochemistry and Physiology
(2004) - et al.
Endectocide exchanges between grazing cattle after pour-on administration of doramectin, ivermectin and moxidectin
International Journal of Parasitology
(2004) - et al.
Ivermectin pharmacokinetics in lactating sheep
Veterinary Parasitology
(2002) - et al.
Comparison of pharmacokinetic profiles of doramectin and ivermectin pour-on formulations in cattle
Veterinary Parasitology
(1999) - et al.
Plasma pharmacokinetics and faecal excretion of ivermectin (Eqvalan® paste) and doramectin (Dectomax®, 1%) following oral administration in donkeys
Research in Veterinary Science
(2005) - et al.
Licking behaviour and environmental contamination arising from pour-on ivermectin for cattle
International Journal of Parasitology
(2001) - et al.
Pharmacokinetic evaluation of four generic formulations in calves
Veterinary Parasitology
(2004) - et al.
Ivermectin disposition kinetics after subcutaneous and intramuscular administration of an oil-based formulation to cattle
Veterinary Parasitology
(1999) - et al.
Comparative distribution of ivermectin and doramectin to parasite location tissues in cattle
Veterinary Parasitology
(2000) - et al.
Effect of parasitism with Nematodirus battus on the pharmacokinetics of levamisole, ivermectin, and netobimin
Veterinary Parasitology
(1991)
Pharmacokinetics of doramectin and ivermectin after oral administration in horses
The Veterinary Journal
Fecal excretion profile of moxidectin and ivermectin after oral administration in horses
The Veterinary Journal
The effect of level of feed intake on the pharmacokinetic disposition and efficacy of ivermectin in sheep
Journal of Veterinary Pharmacology and Therapeutics
Ivermectin in goat plasma and milk after subcutaneous injection
Annales de Recherches Vétérinaires
Persistence of ivermectin in plasma and faeces following administration of a sustained-release bolus to cattle
Research in Veterinary Science
Microdose d´ivermectine chez la vaca laitière: concentrations plasmatiques et rèsidus dans le lait
Recueil de Médecine Vétérinaire
Metabolic profile of ivermectin in goats: an in vivo and in vitro evaluation
The use of ivermectin in horses: research and clinical observations
Compendium on Continuing Education
Stability of ivermectin in rumen fluids
Journal of Veterinary Pharmacology and Therapeutics
Persistent anthelmintic activity of ivermectin in cattle
The Veterinary Record
Comparative pharmacokinetics of doramectin and ivermectin in sheep
Journal of Veterinary Pharmacology and Therapeutics
The comparative serum disposition kinetics of subcutaneous administration of doramectin, ivermectin and moxidectin in the Australian merino sheep
Journal of Veterinary Pharmacology and Therapeutics
Persistent anthelmintic effect of ivermectin in cattle
The Veterinary Record
Use of ivermectin in cattle, sheep, goats, and swine
The pharmacodynamics of ivermectin in sheep and cattle
Journal of Veterinary Pharmacology and Therapeutics
Ivermectin and Abamectin
Ivermectin: a review of efficacy and safety
Journal of Veterinary Pharmacology and Therapeutics
Thermal and long-term freezing stability of ivermectin residues in sheep milk
European Food Research and Technology
Comparative metabolic disposition of ivermectin in fat tissues of cattle, sheep, and rats
Drug Metabolism and Disposition
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