Role of ABC Transporters in Veterinary Medicine: Pharmaco- Toxicological Implications

Author(s): Guillermo Virkel*, Mariana Ballent, Carlos Lanusse, Adrián Lifschitz*.

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 7 , 2019

  Journal Home
Translate in Chinese
Submit Manuscript
Submit Proposal


Unlike physicians, veterinary practitioners must deal with a number of animal species with crucial differences in anatomy, physiology and metabolism. Accordingly, the pharmacokinetic behaviour, the clinical efficacy and the adverse or toxic effects of drugs may differ across domestic animals. Moreover, the use of drugs in food-producing species may impose a risk for humans due to the generation of chemical residues in edible products, a major concern for public health and consumer's safety. As is clearly known in human beings, the ATP binding cassette (ABC) of transport proteins may influence the bioavailability and elimination of numerous drugs and other xenobiotics in domestic animals as well. A number of drugs, currently available in the veterinary market, are substrates of one or more transporters. Therefore, significant drug-drug interactions among ABC substrates may have unpredictable pharmacotoxicological consequences in different species of veterinary interest. In this context, different investigations revealed the major relevance of P-gp and other transport proteins, like breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), in both companion and livestock animals. Undoubtedly, the discovery of the ABC transporters and the deep understanding of their physiological role in the different species introduced a new paradigm into the veterinary pharmacology. This review focuses on the expression and function of the major transport proteins expressed in species of veterinary interest, and their impact on drug disposition, efficacy and toxicity.

Keywords: ATP binding cassette transporters, P-glycoprotein, breast cancer resistance protein, multidrug resistance- associated proteins, xenobiotic transport, domestic animals.

Stewart, J.; Gorman, N. Multi-drug resistance genes in the management of neoplastic disease. J. Vet. Intern. Med., 1991, 5(4), 239-247.
Moore, A.; Leveille, C.; Reimann, K.; Shu, H.; Arias, I. The expression of P-glycoprotein in canine lymphoma and its association with multidrug resistance. Cancer Invest., 1995, 13(5), 475-479.
Mealey, K.; Bentjen, S.; Gay, J.; Cantor, G. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics, 2001, 11(8), 727-733.
Paul, A.; Tranquilli, W.; Seward, R.; Todd, K.; DiPietro, J. Clinical observations in collies given ivermectin orally. Am. J. Vet. Res., 1987, 48(4), 684-685.
Tranquilli, W.; Paul, A.; Seward, R. Ivermectin plasma concentrations in collies sensitive to ivermectin-induced toxicosis. Am. J. Vet. Res., 1989, 50(5), 769-770.
Koritz, G.D. Influence of ruminant gastrointestinal physiology on the pharmacokinetics of drugs in dosage forms administered orally. In Veterinary Pharmacology and Toxicology. Eds Ruckebusch Y, Toutain P, Koritz GD MTP Press Limited, Lancaster, England. 1983, pp 151-164.
Cermak, R. Effect of dietary flavonoids on pathways involved in drug metabolism. Exp. Opin. Drug Met., 2008, 4, 17-35.
Li, Y.; Paxton, J.W. The effects of flavonoids on the ABC transporters: consequences for the pharmacokinetics of substrate drugs. Exp. Opin. Drug Met., 2013, 9, 267-285.
Haslam, I.S.; Simmons, N.L. Expression of the ABC transport proteins MDR1 (ABCB1) and BCRP (ABCG2) in bovine rumen. J. Comp. Physiol. B, 2014, 184, 673-681.
McKellar, Q.; Benchaoui, H. Avermectins and milbemycins. J. Vet. Pharmacol. Ther., 1996, 19, 331-351.
Lanusse, C.; Lifschitz, A.; Virkel, G.; Alvarez, L.; Sanchez, S.; Sutra, J.F.; Galtier, P.; Alvinerie, M. Comparative plasma disposition kinetics of ivermectin, moxidectin and doramectin in cattle. J. Vet. Pharmacol. Ther., 1997, 20, 91-99.
Prichard, R.; Ménez, C.; Lespine, A. Moxidectin and ivermectin: Consanguinity but not identity. Int. J. Parasitol. Drugs Drug Resist., 2012, 2, 134-153.
Lespine, A.; Martin, S.; Dupuy, J.; Roulet, A.; Pineau, T.; Orlowski, S.; Alvinerie, M. Interaction of macrocyclic lactones with P-glycoprotein: structure- affinity relationship. Eur. J. Pharm. Sci., 2007, 30, 84-94.
Eneroth, A.; Astrom, E.; Hoogstraate, J.; Schrenk, D.; Conrad, S.; Kauffmann, H.M.; Gjellan, K. Evaluation of a vincristine resistant Caco-2 cell line for use in a calcein AM extrusion screening assay for P-glycoprotein interaction. Eur. J. Pharm. Sci., 2001, 12, 205-214.
Lennernäs, H. Human jejunal effective permeability and its correlation with preclinical drug absorption models. J. Pharm. Pharmacol., 1997, 49, 627-638.
Davis, J.L.; Little, D.; Blikslager, A.T.; Papich, M.G. Mucosal permeability of water-soluble drugs in the equine jejunum: a preliminary investigation. J. Vet. Pharmacol. Ther., 2006, 29, 379-385.
Ballent, M.; Lifschitz, A.; Virkel, G.; Maté, L.; Sallovitz, J.; Lanusse, C. Application of the Ussing chamber technique to assess P-glycoprotein-mediated intestinal drug transport. J. Vet. Pharmacol. Ther., 2009, 32, 245-246.
Ballent, M.; Maté, L.; Virkel, G.; Sallovitz, J.; Viviani, P.; Lifschitz, A.; Lanusse, C. Intestinal drug transport: ex vivo evaluation of the interactions between ABC transporters and anthelmintic molecules. J. Vet. Pharmacol. Ther., 2014, 37, 332-337.
Short, C.; Flory, W.; Hsieh, L.; Barker, S. The oxidative metabolism of fenbendazole: a comparative study. J. Vet. Pharmacol. Ther., 1988, 11, 50-55.
Souhaili El Amri, H.; Mothe, O.; Totis, M.; Masson, C.; Batt, A.; Delatour, P.; Siest, G. Albendazole sulphonation by rat cytochrome P450c. J. Pharmacol. Exp. Ther., 1988, 246, 758-764.
Virkel, G.; Lifschitz, A.; Sallovitz, J.; Pis, A.; Lanusse, C. Comparative hepatic and extrahepatic enantioselective sulfoxidation of albendazole and fenbendazole in sheep and cattle. Drug Metab. Dispos., 2004, 32, 536-544.
Virkel, G.; Lifschitz, A.; Sallovitz, J.; Pis, A.; Lanusse, C. Assessment of the main metabolism pathways for the flukicidal compound triclabendazole in sheep. J. Vet. Pharmacol. Ther., 2006, 29, 213-223.
Dupuy, J.; Alvinerie, M.; Ménez, C.; Lespine, A. Interaction of anthelmintic drugs with P-glycoprotein in recombinant LLC-PK1-mdr1a cells. Chem. Biol. Interact., 2010, 186, 280-286.
Krishnamurthy, P.; Schuetz, J.D. Role of ABCG2/BCRP in biology and medicine. Annu. Rev. Pharmacol. Toxicol., 2006, 46, 381-410.
Jonker, J.W.; Merino, G.; Musters, S.; van Herwaarden, A.E.; Bolscher, E.; Wagenaar, E.; Mesman, E.; Dale, T.C.; Schinkel, A.H. The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nat. Med., 2005, 11, 127-129.
Wu, H.J.; Luo, J.; Wu, N.; Matand, K.; Zhang, L.J.; Han, X.F.; Yang, B.J. Cloning, sequence and functional analysis of goat ATP-binding cassette transporter G2 (ABCG2). Mol. Biotechnol., 2008, 39, 21-27.
Lindner, S.; Halwachs, S.; Wassermann, L.; Honscha, W. Expression and subcellular localization of efflux transporter ABCG2/BCRP in important tissue barriers of lactating dairy cows, sheep and goats. J. Vet. Pharmacol. Ther., 2013, 36, 562-570.
Wassermann, L.; Halwachs, S.; Lindner, S.; Honscha, K.U.; Honscha, W. Determination of functional ABCG2 activity and assessment of drug-ABCG2 interactions in dairy animals using a novel MDCKII in vitro model. J. Pharm. Sci., 2013, 102, 772-784.
Real, R.; González-Lobato, L.; Baro, M.F.; Valbuena, S.; de la Fuente, A.; Prieto, J.G.; Alvarez, A.I.; Marques, M.M.; Merino, G. Analysis of the effect of the bovine adenosine triphosphate-binding cassette transporter G2 single nucleotide polymorphism Y581S on transcellular transport of veterinary drugs using new cell culture models. J. Anim. Sci., 2011, 89, 4325-4338.
Merino, G.; Jonker, J.W.; Wagenaar, E.; Pulido, M.M.; Molina, A.J.; Alvarez, A.I.; Schinkel, A.H. Transport of anthelmintic benzimidazole drugs by breast cancer resistance protein (BCRP/ABCG2). Drug Metab. Dispos., 2005, 33, 614-618.
Pérez, M.; Blazquez, A.G.; Real, R.; Mendoza, G.; Prieto, J.G.; Merino, G.; Alvarez, A.I. In vitro and in vivo interaction of moxidectin with BCRP/ABCG2. Chem Biol Interact 180:106–112. Perrier D and Gibaldi M (1982) General derivation of the equation for time to reach a certain fraction of steady state. J. Pharm. Sci., 2009, 71, 474-475.
Wassermann, L.; Halwachs, S.; Baumann, D.; Schaefer, I.; Seibel, P.; Honscha, W. Assessment of ABCG2-mediated transport of xenobiotics across the blood-milk barrier of dairy animals using a new MDCKII in vitro model. Arch. Toxicol., 2013, 87, 1671-1682.
Cohen-Zinder, M.; Seroussi, E.; Larkin, D.M.; Loor, J.J.; Everts-van der Wind, A.; Lee, J.H.; Drackley, J.K.; Band, M.R.; Hernandez, A.G.; Shani, M.; Lewin, H.A.; Weller, J.I.; Ron, M. Identification of a missense mutation in the bovine ABCG2 gene with a major effect on the QTL on chromosome 6 affecting milk yield and composition in Holstein cattle. Genome Res., 2005, 15, 936-944.
Otero, J.A.; Real, R.; de la Fuente, A.; Prieto, J.G.; Marques, M.; Alvarez, A.I.; Merino, G. The bovine ATP-binding cassette transporter ABCG2 Y581S single nucleotide polymorphism increases milk secretion of the fluoroquinolone danofloxacin. Drug Metab. Dispos., 2013, 41, 546-549.
Otero, J.A.; Barrera, B.; de la Fuente, A.; Prieto, J.G.; Marqués, M.; Álvarez, A.I.; Merino, G. Short communication: The gain-of-function Y581S polymorphism of the ABCG2 transporter increases secretion into milk of danofloxacin at the therapeutic dose for mastitis treatment. J. Dairy Sci., 2015, 98, 312-317.
Otero, J.A.; Miguel, V.; González-Lobato, L.; García-Villalba, R.; Espín, J.C.; Prieto, J.G.; Merino, G.; Álvarez, A.I. Effect of bovine ABCG2 polymorphism Y581S SNP on secretion into milk of enterolactone, riboflavin and uric acid. Animal, 2016, 10, 238-247.
DeGorter, M.K.; Xia, C.Q.; Yang, J.J.; Kim, R.B. Drug transporters in drug efficacy and toxicity. Annu. Rev. Pharmacol. Toxicol., 2012, 52, 249-273.
Aszalos, A. Drug-drug interactions affected by the transporter protein, P glycoprotein (ABCB1, MDR1) I. Preclinical aspects. Drug Discov. Today, 2007, 12, 833-837.
Liang, X.J. Multidrug transporters and drug targets. Curr. Drug Targets, 2006, 7, 911-921.
Barnes, E.H.; Dobson, R.J.; Barger, I.A. Worm control and anthelmintic resistance: adventures with a model. Parasitol. Today, 1995, 11, 56-63.
Lifschitz, A.; Virkel, G.; Ballent, M.; Sallovitz, J.; Lanusse, C. Combined use of ivermectin and triclabendazole in sheep: in vitro and in vivo characterisation of their pharmacological interaction. Vet. J., 2009, 182, 261-268.
Alvarez, L.; Lifschitz, A.; Entrocasso, C.; Manazza, J.; Mottier, L.; Borda, B.; Virkel, G.; Lanusse, C. Evaluation of the interaction between ivermectin and albendazole following their combined use in lambs. J. Vet. Pharmacol. Ther., 2008, 31, 230-239.
Cromie, L.; Ferry, M.; Couper, A.; Fields, C.; Taylor, S.M. Pharmacokinetics of a novel closantel/ivermectin injection in cattle. J. Vet. Pharmacol. Ther., 2006, 29, 205-211.
Alvinerie, M.; Escudero, E.; Sutra, J.F.; Eeckhoutte, C.; Galtier, P. The pharmacokinetics of moxidectin after oral and and subcutaneous administration to sheep. Vet. Res., 1998, 29, 113-118.
Lifschitz, A.L.; Virkel, G.L.; Sallovitz, J.M.; Pis, A.; Imperiale, F.A.; Lanusse, C.E. Loperamide modifies the tissue disposition kinetics of ivermectin in rats. J. Pharm. Pharmacol., 2004, 56, 61-67.
Kiki-Mvouaka, S.; Ménez, C.; Borin, C.; Lyazrhi, F.; Foucaud-Vignault, M.; Dupuy, J.; Collet, X.; Alvinerie, M.; Lespine, A. Role of P-glycoprotein in the disposition of macrocyclic lactones: a comparison between ivermectin, eprinomectin, and moxidectin in mice. Drug Metab. Dispos., 2010, 38, 573-580.
Molento, M.B.; Lifschitz, A.; Sallovitz, J.; Lanusse, C.; Prichard, R. Influence of verapamil on the pharmacokinetics of the parasitic drugs ivermectin and moxidectin in sheep. Parasitol. Res., 2004, 92, 121-127.
Ballent, M.; Lifschitz, A.; Virkel, G.; Sallovitz, J.M.; Lanusse, C. Involvement of P-glycoprotein on ivermectin kinetic behaviour in sheep: itraconazole-mediated changes on gastrointestinal disposition. J. Vet. Pharmacol. Ther., 2007, 30, 242-248.
Dupuy, J.; Larrieu, G.; Sutra, J.F.; Lespine, A.; Alvinerie, M. Enhancement of moxidectin bioavailability in lamb by a natural flavonoid: quercetin. Vet. Parasitol., 2003, 112, 337-347.
Laffont, C.M.; Toutain, P.L.; Alvinerie, M.; Bousquet-Melou, A. Intestinal secretion is a major route for parent ivermectin elimination in the rat. Drug Metab. Dispos., 2002, 30, 626-630.
Ballent, M.; Lifschitz, A.; Virkel, G.; Sallovitz, J.M.; Lanusse, C. Modulation of the P-glycoprotein-mediated intestinal secretion of ivermectin: in vitro and in vivo assessments. Drug Metab. Dispos., 2006, 34, 457-463.
Riviere, J.E.; Sundlof, S.F. (2009). Chemical residues in tissues of food animals. In Veterinary Pharmacology and Therapeutics. 9th edition. Ed. Wiley-Blackwell pp 1453- 1462.
Mahnke, H.; Ballent, M.; Baumann, S.; Imperiale, F.; von Bergen, M.; Lanusse, C.; Lifschitz, A.L.; Honscha, W.; Halwachs, S. The ABCG2 efflux transporter in the mammary gland mediates veterinary drug secretion across the blood-milk barrier into milk of dairy cows. Drug Metab. Dispos., 2016, 44, 700-708.
Schrickx, J.A.; Fink-Gremmels, J. Implications of ABC transporters on the disposition of typical veterinary medicinal products. Eur. J. Pharmacol., 2008, 585, 510-519.
Escudero, E.; Cárceles, C.M.; Fernandez-Varon, E.; Marin, P.; Benchaoui, H. Pharmacokinetics of danofloxacin 18% in lactating sheep and goats. J. Vet. Pharmacol. Ther., 2007, 30, 572-577.
Ballent, M.; Lifschitz, A.; Virkel, G.; Sallovitz, J.; Maté, L.; Lanusse, C. In vivo and ex vivo assessment of the interaction between ivermectin and danofloxacin in sheep. Vet. J., 2012, 192, 422-427.
Real, R.; Egido, E.; Pérez, M.; Gonzalez-Lobato, L.; Barrera, B.; Prieto, J.G.; Alvarez, A.I.; Merino, G. Involvement of breast cancer resistance protein (BCRP/ABCG2) in the secretion of danofloxacin into milk: Interaction with ivermectin. J. Vet. Pharmacol. Ther., 2011, 34, 313-332.
Pérez, M.; Otero, J.A.; Barrera, B.; Prieto, J.G.; Merino, G.; Alvarez, A.I. Inhibition of ABCG2/BCRP transporter by soy isoflavones genistein and daidzein: Effect on plasma and milk levels of danofloxacin in sheep. Vet. J., 2013, 196, 203-208.
Barrera, B.; González-Lobato, L.; Otero, J.A.; Real, R.; Prieto, J.G.; Álvarez, A.I.; Merino, G. Effects of triclabendazole on secretion of danofloxacin and moxidectin into the milk of sheep: Role of triclabendazole metabolites as inhibitors of the ruminant ABCG2 transporter. Vet. J., 2013, 198, 429-436.
Waller, P. From discovery to development: current industry perspectives for the development of novel methods of helminth control in livestock. Vet. Parasitol., 2006, 139, 1-14.
Prichard, R. Anthelmintic resistance. Vet. Parasitol., 1994, 54, 259-268.
Fiel, C.A.; Saumell, C.A.; Steffan, P.E.; Rodriguez, E.M. Resistance of Cooperia to ivermectin treatments in grazing cattle of the Humid Pampa, Argentina. Vet. Parasitol., 2001, 97, 211-217.
Demeler, J.; Van Zeveren, A.M.; Kleinschmidt, N.; Vercruysse, J.; Höglund, J.; Koopmann, R.; Cabaret, J.; Claerebout, E.; Areskog, M.; von Samson Himmelstjerna, G. Monitoring the efficacy of ivermectin and albendazole against gastrointestinal nematodes of cattle in Northern Europe. Vet. Parasitol., 2009, 160, 109-115.
Xu, M.; Molento, M.; Blackhall, W.; Ribeiro, P.; Beech, R.; Prichard, R. Ivermectin resistance in nematodes may be caused by alteration of P-glycoprotein homolog. Mol. Biochem. Parasitol., 1998, 91, 327-335.
Prichard, R.K.; Roulet, A. ABC transporters and -tubulin in macrocyclic lactones resistance: prospects for marker development. Parasitol., 2007, 134, 1123-1132.
Kwa, M.S.G.; Okoli, M.N. Schulz-Key. H.; Okongkwo, P.O.; Ross, M.H. Use of P-glycoprotein gene probes to investigate antihelmintic resistance in Haemonchus contortus and comparison with Onchocerca volvulus. Int. J. Parasitol., 1998, 28, 1235-1240.
Sangster, N.C.; Bannan, S.C.; Weiss, A.S.; Nulf, S.C.; Klein, R.D.; Geary, T.G. Haemonchus contortus: sequence heterogeneity of internucleotide binding domains from P-glycoproteins. Exp. Parasitol., 1999, 91, 250-257.
Demeler, J.; Krücken, J.; AlGusbi, S.; Ramünke, S.; De Graef, J.; Kerboeuf, D.; Geldhof, P.; Pomroy, W.E.; von Samson-Himmelstjerna, G. Potential contribution of P-glycoproteins to macrocyclic lactone resistance in the cattle parasitic nematode Cooperia oncophora. Mol. Biochem. Parasitol., 2013, 188, 10-19.
Kerboeuf, D.; Blackhall, W.; Kaminsky, R.; von Samson-Himmelstjerna, G. P-glycoprotein in helminths: function and perspectives for anthelmintic treatment and reversal of resistance. Int. J. Antimicrob. Agents, 2003, 22, 332-346.
Blackhall, W.J.; Liu, H.Y.; Xu, M.; Prichard, R.K.; Beech, R.N. Selection at a P-glycoprotein gene in ivermectin- and moxidectin-selected strains of Haemonchus contortus. Mol. Biochem. Parasitol., 1998, 95, 193-201.
Bourguinat, C.; Ardelli, B.F.; Pion, S.D.; Kamgno, J.; Gardon, J.; Duke, B.O.; Boussinesq, M.; Prichard, R.K. P-glycoprotein-like protein, a possible genetic marker for ivermectin resistance selection in Onchocerca volvulus. Mol. Biochem. Parasitol., 2008, 158, 101-111.
Dicker, A.J.; Nisbet, A.J.; Skuce, P.J. Gene expression changes in a P-glycoprotein (Tci-pgp-9) putatively associated with ivermectin resistance in Teladorsagia circumcincta. Int. J. Parasitol., 2011, 41, 935-942.
Williamson, S.M.; Wolstenholme, A.J. P-glycoproteins of Haemonchus contortus: development of real-time PCR assays for gene expression studies. J. Helminthol., 2012, 82, 202-208.
Lloberas, M.; Alvarez, L.; Entrocasso, C.; Virkel, G.; Ballent, M.; Mate, L.; Lanusse, C.; Lifschitz, A. Comparative tissue pharmacokinetics and efficacy of moxidectin, abamectin and ivermectin in lambs infected with resistant nematodes: Impact of drug treatments on parasite P-glycoprotein expression. Int. J. Parasitol. Drugs and Drug Resist., 2013, 3, 20-27.
Prichard, R.; Ménez, C.; Lespine, A. Moxidectin and the avermectins: Consanguinity but not identity. Int. J. Parasitol. Drugs and Drug Resist., 2012, 2, 134-153.
Raza, A.; Kopp, S.R.; Bagnall, N.H.; Jabbar, A.; Kotze, A.C. Effects of in vitro exposure to ivermectin and levamisole on the expression patterns of ABC transporters in Haemonchus contortus larvae. Int. J. Parasitol. Drugs Drug Resist., 2016, 6, 103-115.
Ménez, C.; Mselli-Lakhal, L.; Foucaud-Vignault, M.; Balaguer, P.; Alvinerie, M.; Lespine, A. Ivermectin induces P-glycoprotein expression and function through mRNA stabilization in murine hepatocyte cell line. Biochem. Pharmacol., 2012, 83, 269-278.
Bartley, D.J.; McAllister, H.; Bartley, Y.; Dupuy, J.; Ménez, C.; Alvinerie, M.; Jackson, F.; Lespine, A. P-glycoprotein interfering agents potentiate ivermectin susceptibility in ivermectin sensitive and resistant isolates of Teladorsagia circumcincta and Haemonchus contortus. Parasitol., 2009, 136, 1081-1088.
Raza, A.; Kopp, S.R.; Jabbar, A.; Kotze, A.C. Effects of third generation P-glycoprotein inhibitors on the sensitivity of drug-resistant and -susceptible isolates of Haemonchus contortus to anthelmintics in vitro. Vet. Parasitol., 2015, 211, 80-88.
Bartley, D.J.; Morrison, A.A.; Dupuy, J.; Bartley, Y.; Sutra, J.F.; Ménez, C. Alvinerie; M.; Jackson, F.; Devin, L.; Lespine, A. Influence of Pluronic 85 and ketoconazole on disposition and efficacy of ivermectin in sheep infected with a multiple resistant Haemonchus contortus isolate. Vet. Parasitol., 2012, 187, 464-472.
Lifschitz, A.; Suárez, V.H.; Sallovitz, J.; Cristel, S.L.; Imperiale, F.; Ahoussou, S.; Schiavi, C.; Lanusse, C. Cattle nematodes resistant to macrocyclic lactones: comparative effects of P-glycoprotein modulation on the efficacy and disposition kinetics of ivermectin and moxidectin. Exp. Parasitol., 2010, 125, 172-178.
Lifschitz, A.; Entrocasso, C.; Alvarez, L.; Lloberas, M.; Ballent, M.; Manazza, G.; Virkel, G.; Borda, B.; Lanusse, C. Interference with P-glycoprotein improves ivermectin activity against adult resistant nematodes in sheep. Vet. Parasitol., 2010, 172, 291-298.
Lifschitz, A.; Ballent, M.; Lanusse, C. Macrocyclic lactones and cellular transport-related drug interactions A perspective from in vitro assays to nematode control in the field. Curr. Pharm. Biotechnol., 2012, 13, 912-923.
Neff, M.W.; Robertson, K.R.; Wong, A.K.; Safra, N.; Broman, K.W.; Slatkin, M.; Mealey, K.L.; Pedersen, N.C. Breed distribution and history of canine mdr1-1Delta, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage. Proc. Natl. Acad. Sci. USA, 2004, 101(32), 11725-11730.
Mealey, K.L. Canine ABCB1 and macrocyclic lactones: heartworm prevention and pharmacogenetics. Vet. Parasitol., 2008, 158(3), 215-222.
Mealey, K.L. Therapeutic implications of the MDR-1 gene. J. Vet. Pharmacol. Ther., 2004, 27(5), 257-264.
Lee, J.H.; Shin, Y.J.; Oh, J.H.; Lee, Y.J. Pharmacokinetic interactions of clopidogrel with quercetin, telmisartan, and cyclosporine A in rats and dogs. Arch. Pharm. Res., 2012, 35(10), 1831-1837.
McEntee, M.; Silverman, J.A.; Rassnick, K.; Zgola, M.; Chan, A.O.; Tau, P.T.; Page, R.L. Enhanced bioavailability of oral docetaxel by co-administration of cyclosporin A in dogs and rats. Vet. Comp. Oncol., 2003, 1(2), 105-112.
Schrickx, J.A. Spinosad is a potent inhibitor of canine P-glycoprotein. Vet. J., 2014, 200(1), 195-196.
Snyder, D.E.; Meyer, J.; Zimmermann, A.G.; Qiao, M.; Gissendanner, S.J.; Cruthers, L.R.; Slone, R.L.; Young, D.R. Preliminary studies on the effectiveness of the novel pulicide, spinosad, for the treatment and control of fleas on dogs. Vet. Parasitol., 2007, 150(4), 345-351.
Robertson-Plouch, C.; Baker, K.A.; Hozak, R.R.; Zimmermann, A.G.; Parks, S.C.; Herr, C.; Hart, L.M.; Jay, J.; Hutchens, D.E.; Snyder, D.E. Clinical field study of the safety and efficacy of spinosad chewable tablets for controlling fleas on dogs. Vet. Ther., 2008, 9(1), 26-36.
Dunn, S.T.; Hedges, L.; Sampson, K.E.; Lai, Y.; Mahabir, S.; Balogh, L.; Locuson, C.W. Pharmacokinetic interaction of the antiparasitic agents ivermectin and spinosad in dogs. Drug Metab. Dispos., 2011, 39(5), 789-795.
Holmstrom, S.D.; Totten, M.L.; Newhall, K.B.; Qiao, M.; Riggs, K.L. Pharmacokinetics of spinosad and milbemycin oxime administered in combination and separately per os to dogs. J. Vet. Pharmacol. Ther., 2012, 35(4), 351-364.
Sherman, J.G.; Paul, A.J.; Firkins, L.D. Evaluation of the safety of spinosad and milbemycin 5-oxime orally administered to Collies with the MDR1 gene mutation. Am. J. Vet. Res., 2010, 71(1), 115-119.
Kitamura, Y.; Koto, H.; Matsuura, S.; Kawabata, T.; Tsuchiya, H.; Kusuhara, H.; Tsujimoto, H.; Sugiyama, Y. Modest effect of impaired P-glycoprotein on the plasma concentrations of fexofenadine, quinidine, and loperamide following oral administration in collies. Drug Metab. Dispos., 2008, 36(5), 807-810.
Li, F.; Howard, K.D.; Myers, M.J. Influence of P-glycoprotein on the disposition of fexofenadine and its enantiomers. J. Pharm. Pharmacol., 2017, 69(3), 274-284.
Mealey, K.L.; Waiting, D.; Raunig, D.L.; Schmidt, K.R.; Nelson, F.R. Oral bioavailability of P-glycoprotein substrate drugs do not differ between ABCB1-1Δ and ABCB1 wild type dogs. J. Vet. Pharmacol. Ther., 2010, 33(5), 453-460.
Van der Heyden, S.; Vercauteren, G.; Daminet, S.; Paepe, D.; Chiers, K.; Polis, I.; Waelbers, T.; Hesta, M.; Schauvliege, S.; Wegge, B.; Ducatelle, R. Expression of P-glycoprotein in the intestinal epithelium of dogs with lymphoplasmacytic enteritis. J. Comp. Pathol., 2011, 145(2-3), 199-206.
Patel, J.; Mitra, A.K. Strategies to overcome simultaneous P-glycoprotein mediated efflux and CYP3A4 mediated metabolism of drugs. Pharmacogenomics, 2001, 2, 401-415.
Suzuyama, N.; Katoh, M.; Takeuchi, T.; Yoshitomi, S.; Higuchi, T.; Asashi, S.; Yokoi, T. Species differences of inhibitory effects on P-glycoprotein-mediated drug transport. J. Pharm. Sci., 2007, 96(6), 1609-1618.
Myers, M.J.; Martinez, M.; Li, H.; Qiu, J.; Troutman, L.; Sharkey, M.; Yancy, H.F. Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study. Drug Metab. Dispos., 2015, 43(9), 1392-1407.
Mealey, K.L.; Dassanayake, S.; Burke, N.S. Establishment of a cell line for assessing drugs as canine P-glycoprotein substrates: proof of principle. J. Vet. Pharmacol. Ther., 2017 in press
Swain, M.D.; Orzechowski, K.L.; Swaim, H.L.; Jones, Y.L.; Robl, M.G.; Tinaza, C.A.; Myers, M.J.; Jhingory, M.V.; Buckely, L.E.; Lancaster, V.A.; Yancy, H.F. P-gp substrate-induced neurotoxicity in an Abcb1a knock-in/Abcb1b knock-out mouse model with a mutated canine ABCB1 targeted insertion. Res. Vet. Sci., 2013, 94(3), 656-661.
Coelho, J.C.; Tucker, R.; Mattoon, J.; Roberts, G.; Waiting, D.K.; Mealey, K.L. Biliary excretion of technetium-99m-sestamibi in wild-type dogs and in dogs with intrinsic (ABCB1-1Delta mutation) and extrinsic (ketoconazole treated) P-glycoprotein deficiency. J. Vet. Pharmacol. Ther., 2009, 32(5), 417-421.
Van Der Heyden, S.; Chiers, K.; Ducatelle, R. Tissue distribution of P-glycoprotein in cats. Anat. Histol. Embryol., 2009, 38(6), 455-460.
Mealey, K.L.; Burke, N.S. Identification of a nonsense mutation in feline ABCB1. J. Vet. Pharmacol. Ther., 2015, 38(5), 429-433.
Ramirez, C.; Minch, J.; Gay, J.; Lahmers, S.; Guerra, D.; Haldorson, G.; Schneider, T.; Mealey, K. Molecular genetic basis for fluoroquinolone-induced retinal degeneration in cats. Pharmacogenet. Genomics, 2011, 21(2), 66-75.
Mealey, K.L. ABCG2 transporter: therapeutic and physiologic implications in veterinary species. J. Vet. Pharmacol. Ther., 2012, 35(2), 105-112.
Schiffman, J.; Breen, M. Comparative oncology: what dogs and other species can teach us about humans with cancer. Philos. Trans. R. Soc. Lond. B Biol. Sci., 1673, 2015(370), (1673). pii: 20140231.
MacEwen, E.G. Spontaneous tumors in dogs and cats: models for the study of cancer biology and treatment. Cancer Metastasis Rev., 1990, 9, 125-136.
Levi, M.; Brunetti, B.; Sarli, G.; Benazzi, C. Immunohistochemical Expression of P-glycoprotein and Breast Cancer Resistance Protein in Canine Mammary Hyperplasia, Neoplasia and Supporting Stroma. J. Comp. Pathol., 2016, 155(4), 277-285.
Honscha, K.; Schirmer, A.; Reischauer, A.; Schoon, H.; Einspanier, A.; Gäbel, G. Expression of ABC-transport proteins in canine mammary cancer: consequences for chemotherapy. Reprod. Domest. Anim., 2009, 44(2), 218-223.
Pawlowski, K.; Mucha, J.; Majchrzak, K.; Motyl, T.; Król, M. Expression and role of PGP, BCRP, MRP1 and MRP3 in multidrug resistance of canine mammary cancer cells. BMC Vet. Res., 2013, 9, 119-129.
Lewis, R.; Fidel, J.; Dassanayake, S.; Court, M.; Burke, N.; Mealey, K. Comparison of chemotherapeutic drug resistance in cells transfected with canine ABCG2 or feline ABCG2. Vet. Comp. Oncol., 2017, 15(2), 411-420.
Khammanivong, A.; Gorden, B.; Frantz, A.; Graef, A.; Dickerson, E. Identification of drug-resistant subpopulations in canine hemangiosarcoma. Vet. Comp. Oncol., 2016, 14(3), 113-125.
Sokolowska, J.; Urbańska, K.; Giziński, S.; Zabielska, K.; Lechowski, R. Immunohistochemical detection of P-glycoprotein in various subtypes of canine lymphomas. Pol. J. Vet. Sci., 2015, 18(1), 123-130.
Zandvliet, M.; Teske, E.; Schrickx, J.; Mol, J. A longitudinal study of ABC transporter expression in canine multicentric lymphoma. Vet. J., 2015, 205(2), 263-271.
Zandvliet, M. Canine lymphoma: a review. Vet. Q., 2016, 36(2), 76-104.
Hifumi, T.; Miyoshi, N.; Kawaguchi, H.; Nomura, K.; Yasuda, N. Immunohistochemical detection of proteins associated with multidrug resistance to anti-cancer drugs in canine and feline primary pulmonary carcinoma. J. Vet. Med. Sci., 2010, 72(5), 665-668.
Miyoshi, N.; Tojo, E.; Oishi, A.; Fujiki, M.; Misumi, K.; Sakamoto, H.; Kameyama, K.; Shimizu, T.; Yasuda, N. Immunohistochemical detection of P-glycoprotein (PGP) and multidrug resistance-associated protein (MRP) in canine cutaneous mast cell tumors. J. Vet. Med. Sci., 2002, 64(6), 531-533.
Król, M.; Pawlowski, K.; Majchrzak, K.; Mucha, J.; Motyl, T. Canine mammary carcinoma cell line are resistant to chemosensitizers: verapamil and cyclosporin A. Pol. J. Vet. Sci., 2014, 17(1), 9-17.
Page, R.; Hughes, C.; Huyan, S.; Sagris, J.; Trogdon, M. Modulation of P-glycoprotein-mediated doxorubicin resistance in canine cell lines. Anticancer Res., 2000, 20(5B), 3533-3538.
Hasanabady, M.; Kalalinia, F. ABCG2 inhibition as a therapeutic approach for overcoming multidrug resistance in cancer. J. Biosci., 2016, 41(2), 313-324.
Gameiro, M.; Silva, R.; Rocha-Pereira, C.; Carmo, H.; Carvalho, F.; Bastos, M.; Remião, F. Cellular Models and In Vitro Assays for the Screening of modulators of P-gp, MRP1 and BCRP. Molecules, 2017, 22(4), pii E600.
Krapf, M.; Gallus, J.; Wiese, M. 4-Anilino-2-pyridylquinazolines and -pyrimidines as Highly Potent and Nontoxic Inhibitors of Breast Cancer Resistance Protein (ABCG2). J. Med. Chem., 2017, 60(10), 4474-4495.
Kwak, J.; Lee, S.; Lee, G.; Kim, M.; Ahn, Y.; Lee, J.; Kim, S.; Kim, K.; Lee, M. Selective inhibition of MDR1 (ABCB1) by HM30181 increases oral bioavailability and therapeutic efficacy of paclitaxel. Eur. J. Pharmacol., 2010, 627(1-3), 92-98.
Köhler, S.; Wiese, M. HM30181 Derivatives as Novel Potent and Selective Inhibitors of the Breast Cancer Resistance Protein (BCRP/ABCG2). J. Med. Chem., 2015, 58(9), 3910-3921.
Yang, X.; Liu, K. P-Gp Inhibition-based strategies for modulating pharmacokinetics of anticancer drugs: An update. Curr. Drug Metab., 2016, 17(8), 806-826.
Schmitt, S.; Stefan, K.; Wiese, M. Pyrrolopyrimidine derivatives as novel inhibitors of multidrug resistance-associated protein 1 (MRP1, ABCC1). J. Med. Chem., 2016, 59(7), 3018-3033.
Van der Heyden, S.; Chiers, K.; Vercauteren, G.; Daminet, S.; Wegge, B.; Paepe, D.; Ducatelle, R. Expression of multidrug resistance-associated P-glycoprotein in feline tumours. J. Comp. Pathol., 2011, 144(2-3), 164-169.
Okai, Y.; Nakamura, N.; Matsushiro, H.; Kato, H.; Setoguchi, A.; Yazawa, M.; Okuda, M.; Watari, T.; Hasegawa, A.; Tsujimoto, H. Molecular analysis of multidrug resistance in feline lymphoma cells. Am. J. Vet. Res., 2000, 61(9), 1122-1127.
van Beusekom, C.; Lange, R.; Schrickx, J. A functional model for feline P-glycoprotein. J. Vet. Pharmacol. Ther., 2016, 39(1), 95-97.
Schrickx, J. ABC-transporters in the pig. Ph.D.Thesis, Faculty of Veterinary Medicine, Utrecht University, the Netherlands.. 2006.
Gutmann, H.; Hruz, P.; Zimmermann, C.; Beglinger, C.; Drewe, J. Distribution of breast cancer resistance protein (BCRP/ABCG2) mRNA expression along the human GI tract. Biochem. Pharmacol., 2005, 70, 695-699.
Zimmermann, C.; Gutmann, H.; Hruz, P.; Gutzwiller, J.P.; Beglinger, C.; Drewe, J. Mapping of multidrug resistance gene 1 and multidrug resistance-associated protein isoform 1 to 5 mRNA expression along the human intestinal tract. Drug Metab. Dispos., 2005, 33, 219-224.
Gao, X.; Bhattacharya, S.; Chan, W.K.; Jasti, B.R.; Upadrashta, B.; Li, X. Expression of P-glycoprotein and CYP3A4 along the porcine oral-gastrointestinal tract: implications on oral mucosal drug delivery. Drug Dev. Ind. Pharm., 2014, 40(5), 599-603.
Guo, T.; Huang, J.; Zhang, H.; Dong, L.; Guo, D.; Guo, L.; He, F.; Bhutto, Z.; Wang, L. Abcb1 in Pigs: Molecular cloning, tissues distribution, functional analysis, and its effect on pharmacokinetics of enrofloxacin. Sci. Rep., 2016, 6, 32244.
Baggetto, L.G.; Dong, M.; Bernaud, J.; Espinosa, L.; Rigal, D.; Bonvallet, R.; Marthinet, E. In vitro and in vivo reversal of cancer cell multidrug resistance by the semisynthetic antibiotic tiamulin. Biochem. Pharmacol., 1998, 56, 1219-1228.
Lagas, J.S.; Sparidans, R.W.; van Waterschoot, R.A.; Wagenaar, E.; Beijnen, J.H.; Schinkel, A.H. P-glycoprotein limits oral availability, brain penetration, and toxicity of an anionic drug, the antibiotic salinomycin. Antimicrob. Agents Chemother., 2008, 52(3), 1034-1039.
Plumlee, K.H.; Johnson, B.; Galey, F.D. Acute salinomycin toxicosis of pigs. J. Vet. Diagn. Invest., 1995, 7(3), 419-420.
Kavanagh, N.T.; Sparrow, D.S. Salinomycin toxicity in pigs. Vet. Rec., 1990, 127(20), 507.
Warren, M.S.; Zerangue, N.; Woodford, K.; Roberts, L.M.; Tate, E.H.; Feng, B.; Li, C.; Feuerstein, T.J.; Gibbs, J.; Smith, B.; de Morais, S.M.; Dower, W.J.; Koller, K.J. Comparative gene expression profiles of ABC transporters in brain microvessel endothelial cells and brain in five species including human. Pharmacol. Res., 2009, 59(6), 404-413.
Steimer, A.; Franke, H.; Haltner-Ukomado, E.; Laue, M.; Ehrhardt, C.; Lehr, C.M. Monolayers of porcine alveolar epithelial cells in primary culture as an in vitro model for drug absorption studies. Eur. J. Pharm. Biopharm., 2007, 66(3), 372-382.
Howard, J.; O’Nan, A.; Maltecca, C.; Baynes, R.; Ashwell, M. Differential gene expression across breed and sex in commercial pigs administered fenbendazole and flunixin meglumine. PLoS One, 2015, 10(9), e0137830.
Alizadeh, A.; Braber, S.; Akbari, P.; Garssen, J.; Fink-Gremmels, J. Deoxynivalenol impairs weight gain and affects markers of gut health after low-dose, short-term exposure of growing pigs. Toxins., 2015, 7(6), 2071-2095.
Tydén, E.; Tallkvist, J.; Tjälve, H.; Larsson, P. P-glycoprotein in intestines, liver, kidney and lymphocytes in horse. J. Vet. Pharmacol. Ther., 2009, 32(2), 167-176.
Linardi, R.; Stokes, A.; Andrews, F. The effect of P-glycoprotein on methadone hydrochloride flux in equine intestinal mucosa. J. Vet. Pharmacol. Ther., 2013, 36(1), 43-50.
Olsén, L.; Ingvast-Larsson, C.; Larsson, P.; Broström, H.; Bondesson, U.; Sundqvist, M.; Tjälve, H. Fexofenadine in horses: pharmacokinetics, pharmacodynamics and effect of ivermectin pretreatment. J. Vet. Pharmacol. Ther., 2006, 29(2), 129-135.
Olsén, L.; Ingvast-Larsson, C.; Bondesson, U.; Broström, H.; Tjälve, H.; Larsson, P. Cetirizine in horses: pharmacokinetics and effect of ivermectin pretreatment. J. Vet. Pharmacol. Ther., 2007, 30(3), 194-200.
Linardi, R.L.; Stokes, A.M.; Keowen, M.L.; Barker, S.A.; Hosgood, G.L.; Short, C.R. Bioavailability and pharmacokinetics of oral and injectable formulations of methadone after intravenous, oral, and intragastric administration in horses. Am. J. Vet. Res., 2012, 73(2), 290-295.
Villarino, N.; Martín-Jiménez, T. Pharmacokinetics of macrolides in foals. J. Vet. Pharmacol. Ther., 2013, 36(1), 1-13.
Munic, V.; Kelneric, Z.; Mikac, L.; Erakovic, H. Differences in assessment of macrolide interaction with human MDR1 (ABCB1, P-gp) using rhodamine-123 efflux, ATPase activity and cellular accumulation assays. Eur. J. Pharm. Sci., 2010, 41, 86-95.
Togami, K.; Chono, S.; Morimoto, K. Transport characteristics of clarithromycin, azithromycin and telithromycin, antibiotics applied for treatment of respiratory infections, in Calu-3 cell monolayers as model lung epithelial cells. Pharmazie, 2012, 67, 389-393.
Berlin, S.; Spieckermann, L.; Oswald, S.; Keiser, M.; Lumpe, S.; Ullrich, A.; Grube, M.; Hasan, M.; Venner, M.; Siegmund, W. Pharmacokinetics and Pulmonary Distribution of Clarithromycin and Rifampicin after Concomitant and Consecutive Administration in Foals. Mol. Pharm., 2016, 13(3), 1089-1099.
Giguère, S.; Jacks, S.; Roberts, G.D.; Hernandez, J.; Long, M.T.; Ellis, C. Retrospective comparison of azithromycin, clarithromycin, and erythromycin for the treatment of foals with Rhodococcus equi pneumonia. J. Vet. Intern. Med., 2004, 18, 568-573.
Tamai, I.; Nakanishi, T. OATP transporter-mediated drug absorption and interaction. Curr. Opin. Pharmacol., 2013, 13, 859-863.
Peters, J.; Eggers, K.; Oswald, S.; Block, W.; Lutjohann, D.; Lammer, M.; Venner, M.; Siegmund, W. Clarithromycin is absorbed by an intestinal uptake mechanism that is sensitive to major inhibition by rifampicin: results of a short-term drug interaction study in foals. Drug Metab. Dispos., 2012, 40, 522-528.
Peters, J.; Block, W.; Oswald, S.; Freyer, J.; Grube, M.; Kroemer, H.K.; Lämmer, M.; Lütjohann, D.; Venner, M.; Siegmund, W. Oral absorption of clarithromycin is nearly abolished by chronic comedication of rifampicin in foals. Drug Metab. Dispos., 2011, 39(9), 1643-1649.
Tydén, E.; Bjornstrom, H.; Tjälve, H.; Larsson, P. Expression and localization of BCRP, MRP1 and MRP2 in intestines, liver and kidney in horse. J. Vet. Pharmacol. Ther., 2010, 33(4), 332-340.
Marquez, B.; Van Bambeke, F. ABC multidrug transporters: target for modulation of drug pharmacokinetics and drug-drug interactions. Curr. Drug Targets, 2011, 12(5), 600-620.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [1251 - 1269]
Pages: 19
DOI: 10.2174/0929867325666180201094730
Price: $58

Article Metrics

PDF: 18