Synergism between ivermectin and the tyrosine kinase/ P -glycoprotein inhibitor crizotinib against Haemonchus contortus larvae in vitro

Abstract

2 Graphical abstract3 Highlights:-we examined interaction of P-gp inhibitor crizotinib with ivermectin in Haemonchus contortus larvae in vitro -crizotinib increased the toxicity of ivermectin towards a resistant isolate in migration assays -less synergism observed in larval development assays -assay differences suggest life-stage specific patterns of ivermectin / P-gp interaction.-study highlights potential of P-gp inhibitors to reverse ivermectin resistance AbstractAnthelmintic resistance is a major problem in parasitic nematodes of livestock worldwide. One means to counter resistance is to use synergists that specifically inhibit resistance mechanisms in order to restore the toxicity, and hence preserve the usefulness, of currently available anthelmintics. P-glycoproteins (P-gps) eliminate a wide variety of structurally unrelated xenobiotics from cells, and have been implicated in anthelmintic resistance. Crizotinib is a tyrosine kinase inhibitor under development as a cancer therapeutic.The compound also inhibits P-gps, and has been shown to reverse multidrug resistance in cancer cells. We were therefore interested in determining if the compound was able to increase the sensitivity of Haemonchus contortus larvae to ivermectin, as measured by in vitro larval development and migration assays with a drug-resistant and a -susceptible isolate. In migration assays, co-administration of crizotinib increased the toxicity of ivermectin to resistant larvae (up to 5.7-fold decrease in ivermectin IC50), and rendered the resistant larvae equally or more sensitive to ivermectin than the susceptible isolate. On the other hand, co-administration of crizotinib had no effect on ivermectin sensitivity in the 4 susceptible isolate. In development assays, significant increases in the sensitivity of both the resistant (up to 1.9-fold) and susceptible (up to 1.6-fold) larvae to ivermectin were observed , although the magnitude of the observed synergism was less than seen in migration assays, and the resistant larvae retained significant levels of ivermectin resistance. By highlighting the ability of the P-gp inhibitor crizotinib to increase the sensitivity of H. contortus larvae to ivermectin, this study provides further evidence that P-gp inhibitors are potential tools for modulating the efficacy of anthelmintics. In addition, the differences in the outcomes of the two assays, with 'resistance-breaking' effects being much more marked in migration assays, suggest that some life-stage-specific aspects may exist in the interaction of ivermectin with Pgps in the two worm isolates.

<p>Pharmacokinetic-Based Drug–Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review</p>

“…Crizotinib inhibits the P-gp, OCT1/2, OATPB1/3, OATP2B1, OATP4C1, multidrug and toxin extrusion protein (MATE1), and MATE2-K, but not OAT1/3, or bile salt export pump transporter (BSEP). 11,12,49,50 Razaet al 51 reported that crizotinib significantly increased the sensitivity of P-gp over-expressing cells in response to doxorubicin and paclitaxel. Therefore, crizotinib may have the potential to increase the plasma concentrations of co-administered P-gp substrates, and close clinical surveillance is recommended when crizotinib is administered with these agents.…”

Drug efficacy on zoonotic nematodes of the Anisakidae family: new metabolic data

“…The induction of changes in the functions of metabolic enzymes (or in pumps involved in the removal and inactivation of a drug) may trigger a mechanism of drug resistance. For example, nematodes from the Trichostrongylidae family are resistant to macrocyclic lactones in which the overexpression of genes encoding ABC transporters responsible for removing the pharmaceutical from the parasite has been observed (Raza et al, 2016a(Raza et al, , 2016b(Raza et al, , 2016c.…”

Importance of ABC Transporters in the Survival of Parasitic Nematodes and the Prospect for the Development of Novel Control Strategies

“…Therefore, ABC transporters might be involved in the active efflux of anthelmintic drugs away from their target sites, resulting in decreased drug concentration and increased parasite survival ( Figure 1 ). This has been shown by the increased efficacy of anthelmintic drugs in nematodes using multidrug resistance inhibitors (MDRIs), which inhibit the activity of ABC transporters [ 14 , 15 ]. In addition, it has been suggested that anthelmintics such as ivermectin (IVM), levamisole (LEV) and thiabendazole (TBZ) are substrates of ABC transporters [ 12 , 16 ], and there is considerable evidence that exposure to anthelmintics also modulates the expression patterns of different ABC transporters in nematodes [ 17 , 18 ].…”