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      Treatment of MDR1 Mutant Dogs with Macrocyclic Lactones

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          Abstract

          P-glycoprotein, encoded by the multidrug resistance gene MDR1, is an ATP-driven drug efflux pump which is highly expressed at the blood-brain barrier of vertebrates. Drug efflux of macrocyclic lactones by P-glycoprotein is highly relevant for the therapeutic safety of macrocyclic lactones, as thereby GABA-gated chloride channels, which are confined to the central nervous system in vertebrates, are protected from high drug concentrations that otherwise would induce neurological toxicity. A 4-bp deletion mutation exists in the MDR1 gene of many dog breeds such as the Collie and the Australian Shepherd, which results in the expression of a non-functional P-glycoprotein and is associated with multiple drug sensitivity. Accordingly, dogs with homozygous MDR1 mutation are in general prone to neurotoxicity by macrocyclic lactones due to their increased brain penetration. Nevertheless, treatment of these dogs with macrocyclic lactones does not inevitably result in neurological symptoms, since, the safety of treatment highly depends on the treatment indication, dosage, route of application, and the individual compound used as outlined in this review. Whereas all available macrocyclic lactones can safely be administered to MDR1 mutant dogs at doses usually used for heartworm prevention, these dogs will experience neurological toxicity following a high dose regimen which is common for mange treatment in dogs. Here, we review and discuss the neurotoxicological potential of different macrocyclic lactones as well as their treatment options in MDR1 mutant dogs.

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          Most cited references147

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          Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs.

          We have generated mice homozygous for a disruption of the mdr1a (also called mdr3) gene, encoding a drug-transporting P-glycoprotein. The mice were viable and fertile and appeared phenotypically normal, but they displayed an increased sensitivity to the centrally neurotoxic pesticide ivermectin (100-fold) and to the carcinostatic drug vinblastine (3-fold). By comparison of mdr1a (+/+) and (-/-) mice, we found that the mdr1a P-glycoprotein is the major P-glycoprotein in the blood-brain barrier and that its absence results in elevated drug levels in many tissues (especially in brain) and in decreased drug elimination. Our findings explain some of the side effects in patients treated with a combination of carcinostatics and P-glycoprotein inhibitors and indicate that these inhibitors might be useful in selectively enhancing the access of a range of drugs to the brain.
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            A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants.

            Chinese hamster ovary cells selected for resistance to colchicine display pleiotropic cross-resistance to a wide range of amphiphilic drugs. The drug-resistant phenotype is due to a membrane alteration which reduces the rate of drug permeation. Surface labelling studies reveal that drug-resistant Chinese hamster ovary cell membranes possess a carbohydrate-containing component of 170 000 daltons apparent molecular weight which is not observed in wild type cells. Through studies of the metabolic incorporation of carbohydrate and protein precursors, and through the use of selective proteolysis, this component is shown to be a cell surface glycoprotein. Since this glycoprotein appears unique to mutant cells displaying altered drug permeability, we have designated it the P glycoprotein. The relative amount of surface labelled P glycoprotein correlates with the degree of drug resistance in a number of independent mutant and revertant clones. A similar high molecular weight glycoprotein is also present in drug-resistant mutants from another hamster cell line. Observations on the molecular basis of pleiotropic drug resistance are interpreted in terms of a model wherein certain surface glycoproteins control drug permeation by modulating the properties of hydrophobic membrane regions...
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              The human ATP-binding cassette (ABC) transporter superfamily.

              The transport of specific molecules across lipid membranes is an essential function of all living organisms and a large number of specific transporters have evolved to carry out this function. The largest transporter gene family is the ATP-binding cassette (ABC) transporter superfamily. These proteins translocate a wide variety of substrates including sugars, amino acids, metal ions, peptides, and proteins, and a large number of hydrophobic compounds and metabolites across extra- and intracellular membranes. ABC genes are essential for many processes in the cell, and mutations in these genes cause or contribute to several human genetic disorders including cystic fibrosis, neurological disease, retinal degeneration, cholesterol and bile transport defects, anemia, and drug response. Characterization of eukaryotic genomes has allowed the complete identification of all the ABC genes in the yeast Saccharomyces cerevisiae, Drosophila, and C. elegans genomes. To date, there are 48 characterized human ABC genes. The genes can be divided into seven distinct subfamilies, based on organization of domains and amino acid homology. Many ABC genes play a role in the maintenance of the lipid bilayer and in the transport of fatty acids and sterols within the body. Here, we review the current knowledge of the human ABC genes, their role in inherited disease, and understanding of the topology of these genes within the membrane.
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                Author and article information

                Journal
                Curr Pharm Biotechnol
                Curr Pharm Biotechnol
                CPB
                Current Pharmaceutical Biotechnology
                Bentham Science Publishers
                1389-2010
                1873-4316
                May 2012
                May 2012
                : 13
                : 6
                : 969-986
                Affiliations
                Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University of Giessen, Frank-furter Str. 107, 35392 Giessen
                Author notes
                [* ]Address correspondence to this author at the Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University of Giessen, Frankfurter Str. 107, 35392 Giessen, Germany; Tel: +49 641 9938404; Fax: +49 641 9938419; E-mail: Joachim.M.Geyer@ 123456vetmed.uni-giessen.de
                Article
                CPB-13-969
                10.2174/138920112800399301
                3419875
                22039792
                a954be39-a897-4efe-a188-572d81b5b598
                © 2012 Bentham Science Publishers

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 26 May 2010
                : 6 November 2010
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                p-glycoprotein,mdr1,ivermectin,moxidectin,pharmacogenetics.,milbemycin oxime,dog,ivermectin-sensitive collie

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