Interaction of ivermectin with multidrug resistance proteins (MRP1, 2 and 3)

Lespine, Anne; Dupuy, Jacques; Orlowski, Stéphane; Nagy, Tünde; Glavinas, Hristos; Krajcsi, Péter; Alvinerie, M.

doi:10.1016/j.cbi.2005.11.002

Cited by 111 publications

(79 citation statements)

References 41 publications

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“…This discrepancy in drug-transporter interaction may be due, at least partly, to 1) the drug concentration, 2) the transporter expression level, 3) saturation with endogenous substrates of the pumps that are specific to the tissues, 4) the influence of the lipid environment, and 5) the involvement of influx transporters expressed at the apical pole (or efflux transporters at the basal pole) of the enterocyte that enable MLs to "bypass" entering into the apical plasma membrane. Indeed, ivermectin or moxidectin has been shown to also interact with other transporters such as MRP or BCRP (Lespine et al, 2006;Muenster et al, 2008;Perez et al, 2009), but BCRP does not appear to be a relevant carrier for ivermectin and dmd.aspetjournals.org selamectin (Geyer et al, 2009). However, we cannot exclude the possibility that BCRP, also present at the blood-brain barrier and overexpressed in mdr1ab(Ϫ/Ϫ) mice (Cisternino et al, 2004), contributes partly to the protection of the brain from eprinomectin, thus explaining the relatively low eprinomectin concentration in the brains of P-gp-deficient mice.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Additional evidence from the literature is provided to support the classification of each drug. Reduced CNS activity (Hindmarch et al, 2002) Saquinavir (Sq) Active uptake (Su et al, 2004) Ivermectin (Iv) Additional efflux transporter(s) (Lespine et al, 2006) Ranitidine ( dmd.aspetjournals.org ratio and the [plasma], u /[brain], u ratio differed by more than 3-fold were classified in quadrant IV, indicating less impairment in CNS distribution than indicated by the P-gp efflux ratio. One possible explanation for such drugs is the presence of a compensatory active uptake mechanism.…”

Section: Classification Of Drugs Based On Discrepancies Between In VImentioning

confidence: 99%

Use of Plasma and Brain Unbound Fractions to Assess the Extent of Brain Distribution of 34 Drugs: Comparison of Unbound Concentration Ratios to in Vivo P-Glycoprotein Efflux Ratios

Maurer²,

2007

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ABSTRACT:The P-glycoprotein (P-gp)-deficient mouse model is used to assess the influence of P-gp-mediated efflux on the central nervous system ( The efflux transporter P-glycoprotein (P-gp) attenuates the central nervous system (CNS) distribution of many drugs, including opioids, triptans, protease inhibitors, and antihistamines. One method used to assess the influence of P-gp on the CNS distribution of compounds is the P-gp-deficient mouse model. The P-gp efflux ratio, calculated from the ratio of brain/plasma partition coefficient (K p,brain ) in P-gpdeficient (mdr1aϪ/Ϫ) mice to K p,brain in P-gp-competent (mdr1aϩ/ϩ) mice, reflects the degree to which P-gp-mediated efflux attenuates CNS distribution. However, when other processes influence CNS distribution, the P-gp efflux ratio may be a poor indicator of the degree to which CNS distribution of a compound is impaired.

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“…P-gp expressed on the luminal side of brain endothelial cells plays a very important role in restricting the entry of xenobiotics from the circulating blood into the brain (Matsuoka et al, 1999, Warren et al, 2009). Thus, for example, ivermectin reaches 20-fold higher concentrations in the brains of mice without P-gp (Lespine et al, 2006). The multidrug resistance-associated protein (MRP) 1, 4, 5, and 6 has been detected in primary cultured bovine brain endothelial cells and the bovine brain capillary-enriched fraction (Nies et al, 2004;Yu et al, 2007;Zhang et al, 2000).…”

Section: Bbb Efflux Transporters: Brain-to-blood Efflux Systemmentioning

confidence: 99%