Reversal of P-glycoprotein-associated multidrug resistance by ivermectin

Pouliot, Jean-François; Lheureux, F; Li, Zhi; Prichard, Roger K.; Georges, Elias

doi:10.1016/s0006-2952(96)00656-9

Cited by 163 publications

(110 citation statements)

References 29 publications

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“…A possible interpretation is that ivermectin remains adsorbed to the particulate phase of the digesta during intestinal transit, and thus is not available anymore for absorption in the intestinal fluids. Such a situation has already been described for other compounds such as phenylbutazone [5,16] and is consistent with the high organic-carbon binding constant of ivermectin (K oc = 12600-15700; [11]) and its high hydrophobicity [20]. Ivermectin oral bioavailability was estimated from the model to be 28 ± 13.2%, which is in line with the bioavailability found by Chiu et al [8] in cattle for an intraruminal bolus of ivermectin relative to the subcutaneous route (26%).…”

Section: Discussionsupporting

confidence: 86%

A pharmacokinetic model to document the actual disposition of topical ivermectin in cattle

et al. 2003

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-Ivermectin is a worldwide-used antiparasitic drug largely administered to cattle as a topical formulation (pour-on). The actual plasma and faecal disposition of pour-on ivermectin in cattle was documented using an original pharmacokinetic model, and taking into account the oral ingestion of the topical drug following physiological licking as a secondary route of exposure. Six pairs of monozygotic twin cattle received successively one i.v. and two pour-on administrations of ivermectin at a 3-5-month interval. For one pour-on administration, the twins were separated into an unrestrained group and a group where self-and allo-licking were prevented. Ivermectin concentrations in the plasma and faeces were determined by HPLC. Licking resulted in a high intraand inter-individual variability of systemic exposure after topical application. By the means of pharmacokinetic modelling, we showed that 58-87% of the pour-on dose was ingested, while only 10% was absorbed percutaneously. Approximately 72% of the ingested ivermectin transited directly into the faeces, resulting in a 7-fold higher faecal excretion of the parent drug than in the non-lickers. We conclude that topical administration does not guarantee a controlled drug delivery in cattle. More importantly, the simulations revealed that non-treated cattle could get easily contaminated by allo-licking, raising the public health problem of unexpected drug residues in edible tissues.ivermectin / pour-on / cattle / licking behaviour / pharmacokinetics

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Section: Discussionsupporting

confidence: 86%

A pharmacokinetic model to document the actual disposition of topical ivermectin in cattle

et al. 2003

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“…These latter modulators compete for outward transport of the MDR-related drugs (e.g. cyclosporin A, FK-506, azidopine I-NAPS, and ivermectin) [94,116,170,171].…”

Section: Specific Inhibitorsmentioning

confidence: 99%

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

Safa

2004

CMCACA

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A major problem in cancer treatment is the development of resistance to multiple chemotherapeutic agents in tumor cells. A major mechanism of this multidrug resistance (MDR) is overexpression of the MDR1 product P-glycoprotein, known to bind to and transport a wide variety of agents. This review concentrates on the progress made toward understanding the role of this protein in MDR, identifying and characterizing the drug binding sites of P-glycoprotein, and modulating MDR by P-glycoprotein-specific inhibitors. Since our initial discovery that Pglycoprotein binds to vinblastine photoaffinity analogs, many P-glycoprotein-specific photoaffinity analogs have been developed and used to identify the particular domains of Pglycoprotein capable of interacting with these analogs and other P-glycoprotein substrates. Furthermore, significant advances have been made in delineating the drug binding sites of this protein by studying mutant P-glycoprotein. Photoaffinity labeling experiments and the use of sitedirected antibodies to several domains of this protein have allowed the localization of the general binding domains of some of the cytotoxic agents and MDR modulators on P-glycoprotein. Moreover, site-directed mutagenesis studies have identified the amino acids critical for the binding of some of these agents to P-glycoprotein. Furthermore, equilibrium binding assays using plasma membranes from MDR cells and radioactive drugs have aided our understanding of the modes of drug interactions with P-glycoprotein. Based on the available data, a topological model of Pglycoprotein and the approximate locations of its drug binding sites, as well as a proposed classification of multiple drug binding sites of this protein, is presented in this review.

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“…In the soil nematode Caenorhabditis elegans, P-gp has been shown to be responsible for protection against some toxins (Broeks et al 1995). Pouliot et al (1997), have proposed that ivermectin interacts with the P-gp drug-binding site in cancer cells, and ivermectin may be both a substrate and an inhibitor of P-gp (Didier & Loor 1996). Recent findings showed that ivermectin-selected strains of H. contortus have higher levels of P-gp mRNA than do unselected strains , leading us to suggest that the over expression of P-gp in this parasite may be a consequence of ivermectin selection.…”

Section: Introduction Introduction Introduction Introduction Introducmentioning

confidence: 99%

Effect of multidrug resistance modulators on the activity of ivermectin and moxidectin against selected strains of Haemonchus contortus infective larvae

Molento

Prichard

2001

Pesq. Vet. Bras.

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Reversal of P-glycoprotein-associated multidrug resistance by ivermectin

Cited by 163 publications

References 29 publications

A pharmacokinetic model to document the actual disposition of topical ivermectin in cattle

A pharmacokinetic model to document the actual disposition of topical ivermectin in cattle

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

Effect of multidrug resistance modulators on the activity of ivermectin and moxidectin against selected strains of Haemonchus contortus infective larvae

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