Review
The pharmacokinetics and metabolism of ivermectin in domestic animal species

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Abstract

The pharmacokinetic properties of drugs are closely related to their pharmacological efficacy. The kinetics of ivermectin are characterised, in general terms, by a slow absorption process, a broad distribution in the organism, low metabolism, and slow excretion. The kinetics vary according to the route of administration, formulation, animal species, body condition, age, and physiological status, all of which contribute to differences in drug efficacy. Characterisation of ivermectin kinetics can be used to predict and optimise the value of the parasiticide effects and to design programmes for parasite control. This article reviews the pharmacokinetics of ivermectin in several 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.

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