Comparative plasma dispositions of ivermectin and doramectin following subcutaneous and oral administration in dogs
Introduction
Ivermectin (IVM) and doramectin (DRM) are members of avermectins and have a similar antiparasitic activity at extremely low dosage rates based on a common mode of action. Both chemicals are naturally derived 16-membered macrocyclic lactones (Takiguchi et al., 1980) produced by the soil dwelling actinomycetes, Streptomyces spp. Doramectin differs from IVM through substitution of a cyclohexyl group at the C-25 position (Fig. 1). They are highly effective against nematode and ectoparasitic arthropods in different host species. However, neither molecule is effective against trematodes or cestodes (Shoop et al., 1995).
The pharmacokinetic behaviour of avermectins and milbemycins are significantly affected by route of administration, formulation of the drug, and interspecies and interindividual variation (McKellar and Benchaoui, 1996). These anthelmintics are highly lipophilic substances, and are extensively distributed throughout the body and slowly eliminated from tissues such as liver and fat (Zulalian et al., 1994). Consequently, these compounds have large volumes of distribution (Lanusse et al., 1997). However, bioavailability of endectocides following oral administration may result in lower efficacy and it has been shown that subcutaneous administration of endectocides is a much more efficient route for administration in sheep, cattle and goats as compared to the oral route (Alvinerie, 1997, Gayrard et al., 1999, Laffont et al., 2001, Lespine et al., 2003). Although, a significant first-pass metabolism of IVM is not present in ruminant species (Prichard et al., 1985), oral administration confers relatively lower bioavailability of endectocides because of binding with the organic gut content in sheep (Hennessy et al., 2000) and cattle (Alvinerie et al., 1999).
Plasma dispositions of IVM and DRM have been studied in different animal species. In these studies, it has been demonstrated that DRM has a greater bioavailability and a longer persistence than IVM when administered by the same routes in sheep (Atta and Abo-Shihada, 2000, Barber et al., 2003), cattle (Toutain et al., 1997, Lanusse et al., 1997, Gayrard et al., 1999), horse (Gokbulut et al., 2001, Perez et al., 2002) and donkey (Gokbulut et al., 2005), suggesting that DRM elimination is slower than IVM.
Doramectin is relatively a newer avermectin, licensed for use cattle, sheep and swine, its extra-label use in dogs as an endectocide has been increasing in recent years. The pharmacokinetic behaviour of IVM has been investigated more extensively than that of DRM as IVM is so far the most widely used endectocide across animal species. However, there is a lack of information in the literature on the plasma pharmacokinetics of DRM in dogs. The present study describes the comparative plasma kinetic profile of IVM and DRM in dogs for a 40-day period following oral and subcutaneous administration at a dose of 200 μg/kg bodyweight.
Section snippets
Experimental animals
A total of 20 cross-bred bitches, 2–5 years old and weighing 15–30 kg were used in the study. For the duration of the study, the animals in each group were housed in appropriate pens and each dog was identified by natural markings. Water was supplied ad libitum and animals were fed once daily with an appropriate quantity of feed during the experiment period. This study was approved by Animal Ethic Committee of University of Adnan Menderes.
Treatments and sampling
The animals were allocated into four groups of five such
Results
The analytical procedures for the determination of IVM and DRM plasma concentrations were validated. The linear regression lines for IVM and DRM under the study in the range between 0.25 and 100 ng/ml showed correlation coefficients as 0.996 (IVM) and 0.999 (DRM). The mean extraction recoveries were 96.4% for IVM and 94.29% for DRM. The inter-assay precision of the extraction and chromatographic procedures for IVM and DRM showed coefficients of variations 4.75 and 5.53%, respectively. The
Discussion
The plasma pharmacokinetic profiles obtained following oral and subcutaneous administration of IVM and DRM were different in dogs when compared with the other animals. In ruminants and equine species, DRM produced greater bioavailability and longer persistence compared with IVM when administered by same route of administration (Toutain et al., 1997, Atta and Abo-Shihada, 2000, Barber et al., 2003, Lanusse et al., 1997, Gayrard et al., 1999, Gokbulut et al., 2005, Perez et al., 2002).
The
Conclusion
In conclusion, the present study indicated that oral and subcutaneous treatment of IVM and DRM at doses as high as 200 μg/kg did not cause any clinically detectable adverse affects in dogs. In contrast with ruminants and equine species, oral administration of IVM displayed a significantly higher plasma concentration than that of DRM, whereas no significant differences were observed on the pharmacokinetic parameters between both molecules after subcutaneous administrations. Considering the
Acknowledgements
This study was supported by Scientific Research Committee of Adnan Menderes University (VTF-05005), Aydin, Turkey.
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