Pharmacokinetics and Mammary Elimination of Imidocarb in Sheep and Goats

ABSTRACT

The pharmacokinetics and mammary excretion of imidocarb dipropionate, a therapeutic/prophylactic agent against a variety of tick-borne hemoparasitic diseases in domestic animals, have been investigated in sheep and goats. A commercial formulation of imidocarb dipropionate was injected i.m. at a single dose of 3 mg/kg of body weight in 7 mature lactating ewes and 8 lactating does in good health. Blood samples were collected for 48 h after administration and milk samples were collected every 12 h for 10 d. A weak cation-exchange solid-phase procedure was used to remove imidocarb from plasma. A hexane/isoamyl alcohol liquid-liquid procedure was adopted to extract the drug from the milk of sheep. The same method was used for goat milk after exposing the matrices to enzymatic digestion. The extracted samples were analyzed by HPLC. The i.m. disposition kinetics of imidocarb in the 2 species showed significant differences in the rate of elimination (0.0075 ± 0.002 and 0.025 ± 0.004 L/h in sheep and goats, respectively), being faster in ewes than in does. Nevertheless, a smaller area under the concentration-time curve (12.21 ± 0.76 and 9.49 ± 0.54 µg/mL per h in sheep and goats, respectively), a larger volume of distribution (4.18 ± 0.44 and 7.68 ± 0.57 L/kg in sheep and goats, respectively), and a longer mean residence time (9.07 ± 0.77 and 14.75 ± 2.20 h in sheep and goats, respectively) were found in goats, suggesting a more rapid and effective drug storage in tissues during the first 48 h after the injection. The concentrations of imidocarb in milk of both species were higher than in plasma. However, a fast passage through the blood-milk barrier and a high storage of imidocarb were observed in the milk of ewes, whereas the drug concentrations were not as high nor was the extent of drug penetration from blood to milk as great in the milk of goats (AUC^sub milk 0-48^/AUC^sub plasmu 0-48^ = 2.5 ± 0.45 and 1.26 ± 0.27 in sheep and goat, respectively). Despite the differences in pharmacokinetic behavior, and considering the sensitivity of pathogens to imidocarb, the same dosage regimen can be used for clinical efficacy against Babesia spp. infection in both species. In contrast, the differences in depletion of imidocarb residue in milk and the large variability in mammary drug elimination found in goats suggests that great care should be taken in defining the withdrawal time in small ruminant dairy species.

Key words: imidocarb, pharmacokinetics, milk residues, small ruminant

INTRODUCTION

A variety of tick-borne hemoparasitic diseases occurs in small ruminants, and the economic impact of babesiosis, ehrlichiosis, and anaplasmosis is generally considered striking (Uilenberg, 1995). In endemic areas, control and eradication programs for ticks and tick-borne diseases aim at obtaining enzootic stability and optimizing tick-control strategies, husbandry practices, and effective methods of immunization (Nari, 1995). In many regions, the economic impact created by the widespread presence of tick-borne diseases, such as babesiosis, in sheep and goats warrants proper veterinary care. Veterinary practitioners commonly resort to drugs for elimination of parasites from severely affected animals or for protection of animals traveling from diseasefree areas to endemic regions.

Many drugs have been advocated over the years as therapeutic or prophylactic agents against infection with hemoprotozoa in domestic animals, and among them imidocarb (IMD) is considered the most efficacious and safest of all available medications (Knowles et al., 1980; Kuttler, 1980). Imidocarb is a chemotherapeutic agent of the family of carbanilide derivatives [3,3'-bis (2-imidazolin-2-yl)-carbanilide] with antiprotozoal activity. It is usually administered as dipropionate salt and has been used for over 20 yr in the treatment and prophylaxis of some protozoal diseases such as babesiosis and anaplasmosis in food-producing species (Knowles et al., 1980; Kuttler, 1980; WHO, 1999).

The literature indicates that a high and persistent amount of IMD remains in the animal body, a characteristic that has caused some concern for the production of food for human consumption. The reason for this prolonged persistence has been ascribed both to 1) the resistance of the drug to biotransformation processes, as reported in in vitro studies on cattle (Coldham et al., 1995) and in vivo studies on sheep (Aliu et al., 1977), and 2) a strong binding of the drug to nuclear components, causing the formation of large deposits (especially in the liver and kidney) that release the molecule very slowly (Coldham et al., 1995; Moore et al., 1996). More recent work (Lai et al., 2002) shows that, after i.m. administration of 3.0 mg/kg of IMD dipropionate, high and long-lasting drug levels in sheep …