Vol. 30, Issue 6, 626-630, June 2002

Intestinal Secretion Is a Major Route for Parent Ivermectin Elimination in the Rat

Céline M. Laffont, Pierre-Louis Toutain, Michel Alvinerie, and Alain Bousquet-Mélou

Unité Mixte de Recherche, Institut National de La Recherche Agronomique de Physiopathologie et Toxicologie Expérimentales, Ecole Nationale Vétérinaire de Toulouse, France (C.M.L., P.-L.T., A.B.-M.); and Institut National de la Recherche Agronomique, Station de Pharmacologie et Toxicologie, France (M.A.)

The transepithelial intestinal elimination of ivermectin was studied using the intestinal closed-loop model in the rat. The common bile duct was cannulated, and duodenum, jejunum, and ileum were isolated in situ with their intact blood supplies. Following administration of 100, 200, or 400 µg/kg b.wt. ivermectin via the carotid artery, the elimination of parent ivermectin into the small intestinal lumen over 90 min was approximately 5-fold higher than in bile. The major amount of secreted ivermectin was recovered in the jejunum, but the duodenum showed a higher intestinal elimination capacity than the other intestinal segments with respect to the intestinal length. Systemic coadministration of the P-glycoprotein blocker verapamil significantly reduced the elimination capacity of jejunum by 50%, which resulted in a 30% decrease of ivermectin overall elimination by the small intestine. In contrast, verapamil did not significantly affect ivermectin secretion in duodenum, ileum, or bile in the same animals. Ivermectin small intestinal and biliary clearances were estimated to account for 27 and 5.5% of the total drug clearance, which was evaluated from a parallel in vivo experiment in which rats were given 200 µg/kg b.wt. ivermectin intra-arterially. In conclusion, intestinal secretion plays a greater role than biliary secretion in the overall elimination of ivermectin in the rat, providing major amounts of active drug to the intestinal lumen and to feces. This is discussed in terms of therapeutic efficacy against intestinal parasites in humans and animals and of ecotoxicity resulting from the contamination of livestock dung with parent drug.