Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology
Macrocyclic lactones: distribution in plasma lipoproteins of several animal species including humans
Introduction
Macrocyclic lactones (MLs) are potent parasiticides widely used for control of internal and external parasites in domestic animals and livestock. Ivermectin, the semisynthetic derivative of avermectin B1, is also used in humans for the treatment of onchocerciasis, lymphatic filariasis, and scabies (Tagboto and Townson, 1996, Dourmishev et al., 1998). Commercially available ivermectin, eprinomectin, abamectin, and doramectin belong to the avermectin family, whereas moxidectin is a member of the milbemycin family (Fig. 1) currently under development in humans (Cotreau et al., 2003). These compounds are hydrophobic molecules characterized by a broad spectrum of activity with remarkable long-lasting efficacy. A large number of pharmacokinetic studies are available for these drugs, reporting a large volume of distribution, long residence time, extensive elimination in milk during lactation (Hennessy and Alvinerie, 2002), and an influence of adiposity on their pharmacokinetic behaviour (Craven et al., 2002). Thus, one of the major factors contributing to the disposition of these compounds is certainly the extent of release or exchange between the lipid reserve and bloodstream. Because the presence of MLs in the plasma and at the location of the parasite are closely correlated (Lifschitz et al., 2000), their partitioning into plasma components becomes a determinative factor for drug disposition and efficacy. Regarding their high affinity for fat tissues, we hypothesized that MLs may associate preferentially to lipoproteins in plasma. Lipoproteins are macromolecules of lipid and protein commonly involved in the transport of cholesterol, cholesteryl ester, triacylglycerol, and phospholipid, through vascular and extravascular body fluids. They also transport a wide number of hydrophobic xenobiotics within the bloodstream (Wasan and Cassidy, 1998). The interaction of drugs such as amphotericin B, cyclosporine, annamycin, and nystatin with lipoproteins has been reported to influence their pharmacokinetic behaviour, pharmacological activity, and toxicity (Wasan and Cassidy, 1998). As far as ivermectin is concerned, very few data mentioning that all the systemic drugs were associated with the plasma are available. The binding of ivermectin to serum albumin has been postulated in patients with onchocerciasis (Klotz et al., 1990). In dogs, serum albumin and lipoproteins have been shown to bind ivermectin to a similar extent (Rohrer and Evans, 1990).
The aim of this study was to examine the in vitro partitioning of commercialized MLs into plasma components. In a first step, we have studied the ability of five different MLs belonging to the structurally related avermectin and milbemycin families to associate with plasma components in the goat, representative of ruminants in terms of the plasma lipoprotein profile. In a second step, the ability of moxidectin to associate with plasma components was studied in five different animal species and humans.
Section snippets
Animal maintenance and treatment
Alpine goats (Capra hircus) weighing 25–30 kg (12–15 months, n=10) were housed in our animal facilities in concrete pens, fed barley hay, and commercial concentrates (Toulgrain, France) with free access to water. Three goats were treated with ivermectin (Ivomec; Merial, France) by subcutaneous administration (0.2 mg/kg), while seven goats did not receive any ML treatment. Male pigs (Sus domesticus, n=5) were housed in our animal facilities. Cows (Boss spp., n=5), male sheep (Ovies aries, n=5),
Distribution of different MLs in goat plasma components
Goat plasma samples spiked with different MLs were fractionated using KBr density gradient ultracentrifugation. This technique has been previously validated to separate plasma lipoproteins of different animal species (Terpstra et al., 1981). It allowed rapid and accurate separation of the three major plasma lipoprotein fractions [very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL)] and a lipoprotein-deficient fraction (LPDF), which contained
Discussion
Although the partitioning of hydrophobic drugs into plasma components represents a pivotal step for the drug distribution in the organism, this point has not been documented for MLs. The ability of five different MLs to associate in vitro with plasma components was studied in the goat, which is representative of ruminants as far as the lipoprotein profile is concerned. The three major lipoprotein fractions (VLDL, LDL, and HDL) and a lipoprotein-deficient fraction that contained mainly aqueous
Acknowledgements
We are grateful to Prof. Bertrand P. Perret for helpful discussions.
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