Role of P-Glycoprotein in the Disposition of Macrocyclic Lactones: A Comparison between Ivermectin, Eprinomectin, and Moxidectin in Mice

Abstract

ABSTRACT: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-gpdeficient [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.

Emamectin benzoate (Proclaim®) mediates biochemical changes and histopathological damage in the kidney of male Wistar rats (Rattus norvegicus)

“…Cárcamo et al [36] showed that exposure of rainbow trouts to pharmacological EMB concentrations altered the transcriptional responses of xenobiotic biotransformation proteins and extrusion transporters. EMB increases CYP3A expression in kidney and intestine samples and it is wellknown that CYP3A enzymes participate strongly in drug interactions [37,38]. Probably, the lipophilic nature of EMB and its non-biotransformation may lead to its accumulation in the plasma and produce changes in many functions including renal, nerve and hepatic functions.…”

Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs

“…Characterization of brain tissue ivermectin concentrations in ivermectin-sensitive collies (Pulliam et al, 1985) supports a link between P-gp function and the CNS distribution of ivermectin. The CNS disposition of ivermectin and related macrocyclic lactones has also been linked to P-gp function in rodents (Schinkel et al, 1994;Kwei et al, 1999;Kiki-Mvouaka et al, 2010).…”

Δ2,3 -Ivermectin ethyl secoester, a conjugated ivermectin derivative with leishmanicidal activity but without inhibitory effect on mammalian P-type ATPases

“…As we do not know the fine mechanism of ivermectin inhibition of this enzyme, albeit we reported some details in a previous work (Pimenta et al 2010), it could be argued that ivermectin should penetrate the membrane to interact with some putative intracellular locus of the transmembrane ATPases (Na + ,K + -ATPase and H + ,K + -ATPase). Note that ivermectin is very lipophilic (Log P of 3.217, 4.8, and 5.31 have been reported by Camargo et al 2010;Kiki-Mvouaka et al 2010 andBaynes 2009, respectively), so that it can easily penetrate the plasma membrane and reach the internal loops of these enzymes. It could also penetrate the cell and reach the SERCA, as occurs with thapsigargin, a lipophylic sequiterpene lactone that specifically inhibits this Ca 2+ -ATPase located in the sarco-endoplasmic reticulum.…”