title: Contribution of lymphatic transport to the systemic exposure of orally administered moxidectin in conscious lymph duct-cannulated dogs.
abstract: Moxidectin, a macrocyclic lactone (ML), is a potent parasiticide widely used in veterinary medicine and currently under development for use in humans. The contribution of the lymphatic route to the intestinal absorption and transport of moxidectin to the systemic circulation was evaluated in lymph duct-cannulated dogs. Beagle dogs were operated for lymph duct cannulation and were orally dosed with 38g of corn oil and moxidectin (0.2mg/kg, n=3). The lymph and plasma were collected over 24h and moxidectin and triglyceride concentrations were measured. Similarly, control dogs (n=5) were dosed orally with moxidectin and oil and subsequently with moxidectin intravenously. Pharmacokinetic parameters were calculated for moxidectin in the plasma of the dogs. Moxidectin readily accumulated in the lymph and reached a plateau 8h post-administration, paralleling triglyceride appearance. The percentage of moxidectin recovered in lymph was 22+/-3% of the total administered dose with 92% being associated with triglyceride-rich particles. The systemic bioavailability of oral moxidectin coadministered with lipid was only 40% in the lymph duct-cannulated dogs compared with 71% in the controls. Our data clearly indicate that the lymphatic transport process contributes significantly to the post-prandial intestinal absorption of moxidectin and subsequently to its systemic bioavailability. The lymphatic transport of moxidectin offers potential strategies based on lipid formulations to improve the bioavailability of MLs when administered orally.
authors.affiliation: INRA-UR66, Laboratoire de Pharmacologie-Toxicologie, BP 3, 31931 Toulouse Cedex 9, France. lespine@toulouse.inra.fr
authors.forename: Anne
authors.initials: A
authors.lastname: Lespine
authors.forename: Guillaume
authors.initials: G
authors.lastname: Chanoit
authors.forename: Alain
authors.initials: A
authors.lastname: Bousquet-Melou
authors.forename: Elodie
authors.initials: E
authors.lastname: Lallemand
authors.forename: Firas Mohamad
authors.initials: FM
authors.lastname: Bassissi
authors.forename: Michel
authors.initials: M
authors.lastname: Alvinerie
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Toutain
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001692:Biological Transport; D002404:Catheterization; D002626:Chemistry, Pharmaceutical; D003314:Corn Oil / Q000008:administration & dosage; D004285:Dogs; D007408:Intestinal Absorption; D008208:Lymphatic System / Q000378:metabolism*; D018942:Macrolides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D023421:Models, Animal; D019518:Postprandial Period; D013897:Thoracic Duct / Q000601:surgery; D014280:Triglycerides / Q000097:blood
chemical_list: D000871:Anthelmintics; D018942:Macrolides; D014280:Triglycerides; D003314:Corn Oil; C027837:moxidectin