Role of P-glycoprotein in the disposition of macrocyclic lactones: A comparison between ivermectin, eprinomectin, and moxidectin in mice.
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.
Kiki-Mvouaka
Solange
S
Institut National de la Recherche Agronomique, Toulouse, France.
Ménez
Cécile
C
Borin
Christiane
C
Lyazrhi
Faouri
F
Foucaud-Vignault
Magali
M
Dupuy
Jacques
J
Collet
Xavier
X
Alvinerie
Michel
M
Lespine
Anne
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D000871:Anthelmintics / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018942:Macrolides / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010477:Perfusion; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000871:Anthelmintics; D018942:Macrolides; D007559:Ivermectin; C101434:eprinomectin; C027837:moxidectin