PT - JOURNAL ARTICLE AU - Solange Kiki-Mvouaka AU - Cécile Ménez AU - Christiane Borin AU - Faouri Lyazrhi AU - Magali Foucaud-Vignault AU - Jacques Dupuy AU - Xavier Collet AU - Michel Alvinerie AU - Anne Lespine TI - Role of P-Glycoprotein in the Disposition of Macrocyclic Lactones: A Comparison between Ivermectin, Eprinomectin, and Moxidectin in Mice AID - 10.1124/dmd.109.030700 DP - 2010 Apr 01 TA - Drug Metabolism and Disposition PG - 573--580 VI - 38 IP - 4 4099 - http://dmd.aspetjournals.org/content/38/4/573.short 4100 - http://dmd.aspetjournals.org/content/38/4/573.full SO - Drug Metab Dispos2010 Apr 01; 38 AB - Macrocyclic lactones (MLs) are lipophilic anthelmintics and substrates for P-glycoprotein (P-gp), an ATP-binding cassette transporter involved in drug efflux out of both host and parasites. To evaluate the contribution of P-gp to the in vivo kinetic disposition of MLs, the plasma kinetics, brain concentration, and intestinal excretion of three structurally different MLs (ivermectin, eprinomectin, and moxidectin) were compared in wild-type and P-gp-deficient [mdr1ab(−/−)] mice. Each drug (0.2 mg/kg) was administered orally, intravenously, or subcutaneously to the mice. Plasma, brain, and intestinal tissue concentrations were measured by high-performance liquid chromatography. The intestinal excretion rate after intravenous administration was determined at different levels of the small intestine by using an in situ intestinal perfusion model. P-gp deficiency led to a significant increase in the area under the plasma concentration-time curve (AUC) of ivermectin (1.5-fold) and eprinomectin (3.3-fold), whereas the moxidectin AUC was unchanged. Ivermectin and to a greater extent eprinomectin were both excreted by the intestine via a P-gp-dependent pathway, whereas moxidectin excretion was weaker and mostly P-gp-independent. The three drugs accumulated in the brains of the mdr1ab(−/−) mice, but eprinomectin concentrations were significantly lower. We concluded that eprinomectin disposition in mice is controlled mainly by P-gp efflux, more so than that of ivermectin, whereas moxidectin disposition appears to be mostly P-gp-independent. Given that eprinomectin and ivermectin have higher affinity for P-gp than moxidectin, these findings demonstrated that the relative affinity of MLs for P-gp could be predictive of the in vivo kinetic behavior of these drugs. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics