Modulation of the P-Glycoprotein-Mediated Intestinal Secretion of Ivermectin: In Vitro and in Vivo Assessments

Ballent, Mariana; Lifschitz, Adrián Luis; Virkel, G.; Sallovitz, Juan Manuel; Lanusse, Carlos

doi:10.1124/dmd.105.007757

Cited by 85 publications

(55 citation statements)

References 27 publications

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“…Ivermectin is eliminated mostly unchanged in bile and feces (González Canga et al, 2009) and so, as a P-gp substrate, it is a candidate for secretion by the liver or intestine. Thus, the possibility that systemic ivermectin concentrations increase as a result of spinosad inhibition of secretion should be considered, especially because ivermectin is known to undergo P-gp-mediated exsorption in rodents (Sparreboom et al, 1997;Laffont et al, 2002;Ballent et al, 2006). As an alternative, the increase in the dog ivermectin C max and lack of change in the terminal half-life could suggest that spinosad increased the oral fraction of ivermectin absorbed.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs

et al. 2011

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ABSTRACT:Neurological side effects consistent with ivermectin toxicity have been observed in dogs when high doses of the common heartworm prevention agent ivermectin are coadministered with spinosad, an oral flea prevention agent. Based on numerous reports implicating the role of the ATP-binding cassette drug transporter P-glycoprotein (P-gp) in ivermectin efflux in dogs, an in vivo study was conducted to determine whether ivermectin toxicity results from a pharmacokinetic interaction with spinosad. Beagle dogs were randomized to three groups treated orally in parallel: Treatment group 1 (T01) received ivermectin (60 g/kg), treatment group 2 (T02) received spinosad (30 mg/kg), and treatment group 3 (T03) received both ivermectin and spinosad. Whereas spinosad pharmacokinetics were unchanged in the presence of ivermectin, ivermectin plasma pharmacokinetics revealed a statistically significant increase in the area under the curve (3.6-fold over the control) when ivermectin was coadministered with spinosad. The majority of the interaction is proposed to result from inhibition of intestinal and/or hepatic P-gp-mediated secretory pathways of ivermectin. Furthermore, in vitro Transwell experiments with a human multidrug resistance 1-transfected Madin-Darby canine kidney II cell line showed polarized efflux at concentrations <2 M, indicating that spinosad is a high-affinity substrate of P-gp. In addition, spinosad was a strong inhibitor of the P-gp transport of digoxin, calcein acetoxymethyl ester (IC 50 ‫؍‬ 3.2 M), and ivermectin (IC 50 ‫؍‬ 2.3 M). The findings suggest that spinosad, acting as a P-gp inhibitor, increases the risk of ivermectin neurotoxicity by inhibiting secretion of ivermectin to increase systemic drug levels and by inhibiting P-gp at the blood-brain barrier.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs

et al. 2011

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“…On the contrary, for moxidectin, the contribution of P-gp in these processes was weak as shown by the lack of change of moxidectin plasma kinetics in mdr1ab(Ϫ/Ϫ) mice. P-gp is known to be partly responsible for MLs elimination by the fecal route via intestinal excretions (Laffont et al, 2002;Ballent et al, 2006). Thus, we have compared the capacity of the intestine to eliminate these drugs.…”

Section: Discussionmentioning

confidence: 99%

“…MLs are poorly metabolized (Chiu et al, 1987;Alvinerie et al, 2001) and are good substrates and potent inhibitors of P-gp (Didier and Loor, 1996;Pouliot et al, 1997;Lespine et al, 2007). P-gp protects the brain from MLs by limiting their penetration across the blood-brain barrier and thus their subsequent neurotoxicity (Schinkel et al, 1994;Lankas et al, 1997;Roulet et al, 2003), and it contributes to the elimination of ivermectin via intestinal excretion (Laffont et al, 2002;Ballent et al, 2006). Moreover, P-gp-mediated drug efflux has been suggested as a protection mechanism in nematodes, and several P-gp homologs are overex-pressed in ivermectin resistance (Prichard and Roulet, 2007).…”

mentioning

confidence: 99%

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

Kiki-Mvouaka¹,

Ménez²,

Borin³

et al. 2010

Drug Metab Dispos

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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.

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“…This model has also been reported to be applicable to both rat and mouse, and to study the phase I and phase II metabolism as well as transport. Inhibition studies of enzymes and transporters, such as CYP3A4 and MDR1, have also been reported (Hashimoto et al, 1998;Ballent et al, 2006). However, the major disadvantage of this model is that the lack of blood and nerve supply can lead to a rapid loss of tissue viability.…”

Section: Animal Tissue-based In Vitro Methodmentioning

confidence: 99%

Intestinal Perfusion Methods for Oral Drug Absorptions

Zhu¹,

Jeong

2011

Oral Bioavailability

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Modulation of the P-Glycoprotein-Mediated Intestinal Secretion of Ivermectin: In Vitro and in Vivo Assessments

Cited by 85 publications

References 27 publications

Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs

Pharmacokinetic Interaction of the Antiparasitic Agents Ivermectin and Spinosad in Dogs

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

Intestinal Perfusion Methods for Oral Drug Absorptions

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