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Publication Date: 2014-06-20
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Correa Salgado, R. A., & Castaño, E. (2014). Analysis of the canine ABCB1-1▲ mutation and its therapeutic and toxicological implications. Biosalud, 13(1), 65–75. Retrieved from https://revistasojs.ucaldas.edu.co/index.php/biosalud/article/view/4688
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Abstract
We conducted a review of the results of the studies of the last ten years from the data bases BBCS-LILACS, IB- PsycINFO, IB-SSCI, IB.SciELO, SCOPUS and SCIRUS, about the therapeutic implications of the gene mutation ABCB1 in dogs. This mutation is responsible for the absence of the glycoprotein P in the blood-brain barrier, depriving the brain of an efflux pump to protect against various xenobiotics. Furthermore, we described the pharmacokinetic changes and drug poisoning resulting from this mutation. We also present a list of drug substrates for the glycoprotein P and the medications that can inhibit said glycoprotein, all of them capable of inducing severe side effects in dogs with the mutation.
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References
Mealey K, Greene S, Bagley R, Gay J, Tucker R, Gavin P. et al. P-glycoprotein contributes to the blood-brain but not blood-cerebrospinal fluid barrier in a spontaneous canine P-glycoprotein knockout model. Drug Metabolism and Disposition 2008; 36: 1073-1079.
Schinkel A. P-Glycoprotein, a gatekeeper in the blood-brain barrier. Advance Drug Delivery Reviews 1999; 36: 179-194.
Fromm M. Importance of P-glycoprotein at blood-tissue barriers. TRENDS in Pharmacological Sciences 2004; 25 (8): 423-429.
Ueda K, Cardalleri C, Gottesman M, Pastan I. Expression of a full-length cDNA for the human “MDR1” gene confers resistance to colchicines, doxorubicin and vinblastine. Proc. Nalt. Acad. Sci. USA 1987; 84: 3004-3008.
Fromm M. Importance of P-glycoprotein for drug disposition in humans. European Journal of Clinical Investigation 2003; 33: 6-9.
Thiebaut F, Tsuruo T, Hamada H, Gottesman M, Pastan I, Willingham M. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sci. 1987; 84: 7735-7738.
Fromm M. P-glycoprotein: A defense mechanism limiting oral bioavailability and CNS accumulation of drugs. International Journal of Clinical Pharmacology and Therapeutics 2000; 38: 69-74.
Loscher W, Potschka H. Role of drug efllux transporters in the brain for drug disposition and treatment of brain diseases. Progress in Neurobiology 2005; 76: 22-76.
Lankas G, Wise LD, Cartwright M, Pippert T, Umbenhauer D. Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reproductive Toxicology 1998; 12 (4): 457-463.
Schrickx J, Fink-gremmels J. Implications of ABC transporters on the disposition of typical veterinary medicinal products. European Journal of Pharmacology 2008; 585: 510-519.
Geyer J, Doring B, Godoy J, Leidolf R, Moritz A, Petzinger E. Frequency of the nt230(del4) MDR1 mutation in collies and related dogs breeds in Germany. J. Vet. Pharmacol. Therap. 2005; 28: 545-551.
Dean M. The genetics of ATP-binding cassette transporters. Methods in Enzymology 2005; 400: 409-429.
Klintzsch S, Meerkamp K, Doring B, Geyer J. Detection of the nt230(del4) MDR1 mutation in dogs by a fluorogenic 5’nuclease TaqMan allelic discrimination method. The Veterinary Journal 2010; 185: 272-277.
Geyer J, Doring B, Godoy J, Moritz A, Petzinger E. Development of a PCR-based diagnostic test detecting a nt230(del4) MDR1 mutation in dogs: Verification in a moxidectin-sensitive Australian shepherd. J. Vet. Pharmacol. Therap. 2005; 28: 95-99.
Mealey K, Meurs K, Breed distribution of the ABCB1-1Δ (multidrug sensitivity) polymorphism among dogs undergoing ABCB1 genotiping. Journal of the American Veterinary Medical Association 2008; 233: 921-924.
Menez 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. Biochemical Pharmacology 2012; 83: 269-278.
Mealey K. Canine ABCB1 and macrocyclic lactones: Heartworm prevention and pharmacogenetics. Veterinary Parasitology 2008; 158: 215-222.
Lespine A, Menez C, Bourguinat C, Prichard R. P-glycoproteins and other multidrug resistance transporters in the pharmacology of anthelmintics: Prospects for reversing transport-dependent anthelmintic resistance. International Journal of Parasitology: Drugs and Drug Resistance 2011; 10: 1-18.
Hugnet C, Bentjen S, Mealey K. Frequency of the mutant MDR1 allele associated with multidrug sensitivity in a sample of collies from France. J. Vet. Pharmacol. Therap. 2004; 27: 227-229.
Mealey K, Munyard K, Bentjen S. Frequency of the mutant MDR1 allele associated with multidrug sensitivity in a sample of herding breed dogs living in Australia. Veterinary Parasitology 2005; 131: 193-196.
Roulet A, Puel O, Gesta S, Lepage J, Drag M, Soll M. et al. MDR1-deficient genotype in collie dogs hypersensitive to the P-glycoprotein substrate ivermectin. European Journal of Pharmacology 2003; 460: 85-91.
Gramer I, Leidolf R, Doring B, Klintzsch S, Kramer E, Yalcin E. et al. Breed distribution of the nt230(del4) MDR1 mutation in dogs. The Veterinary Journal 2011; 189: 67-71.
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: 727-733.
Kitamura Y, Koto H, Matsuura S, Kawabata T, Tsuchiya H, Kusuhara H. et al. Modest effect of impaired P-glycoprotein on the plasma concentration of fexofenadine, quinidine and loperamide following oral administration in collies. Drug Metabolism and Disposition 2008; 36: 807-810.
Nelson O, Carsten E, Bentjen S, Mealey K. Ivermectin toxicity in an Australian shepherd dog with the MDR1 mutation associated with ivermectin sensitivity in collies. J Vet Intern Med. 2003; 17: 354-356.
Geyer J, Klintzsch S, Meerkamp M, Wohlke A, Distl O, Moritz A. et al. Detection of the nt230(del4)MDR1 mutation in White Swiss Shepherd dogs: Case reports of doramectin toxicosis, breed predispositions, and microsatellite analysis. J. Vet. Pharmacol. Therap. 2007; 30: 482-485.
Fecht S, Wohlke A, Hamann H, Distl O. Analysis of the canine MDR1 - 1Δ mutation in the dog breed Elo. J. Vet. Med. A. 2007; 54: 401- 405.
Baars C, Leeb T, Klopmann T, Tipold A, Potschka H. Allele-specific polymerase chain reaction diagnostic test for the functional MDR1 polymorphism in dog. The Veterinary Journal 2008; 177: 394-397.
Tappin S, Goodfellow M, Peters I, Day M, Vall E, Bentjen S. et al. Frequency of the mutant MDR1 allele associated with multidrug sensitivity in dogs in the United Kingdom. In BSAVA congress, scientific proceedings, veterinary programs; 2008.
Mealey K, Bentjen S, Waiting D. Frequency of the mutant MDR1 allele associated whit ivermectin sensitivity in a sample population of collies from the northwestern United States. American Journal of Veterinary Research 2002; 63: 479-481.
Neff M, Robertson K, Wong A, Safra N, Broman K, Slatkin M. et al. Breed distribution and history of canine MDR1-1Δ, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage. PNAS 2004; 101 (32): 11725-11730.
Mealey K. Pharmacogenetics. Vet Clin Small Anim. 2006; 36: 961- 973.
Martinez M, Modric S, Sharkey M, Troutman L, Walker L, Mealey K. The pharmacogenomics of P-glycoprotein and its role in veterinary medicine. J. Vet. Pharmacol. Therap. 2008; 31: 285-300.
Sherman J. Understanding the impact of P-glycoprotein mutation on canine health. The Veterinary Journal 2011; 190: 13-14.
Coelho J, Tucker R, Mattoon J, Roberts G, Waiting D, Mealey K. Biliary excretion of technetium-99msestamibi in wild-type dogs and in dogs with intrinsic (ABCB1 -1Δ mutation) and extrinsic (ketoconazole treated) P-glycoprotein deficiency. J. Vet. Pharmacol. Therap. 2009; 32: 417-421.
Gokbulut C, Karademir U, Boyacioglu M, McKellar Q. Comparative plasma dispositions of ivermectin and doramectin following subcutaneous and oral administration in dogs. Veterinary Parasitology 2006; 135: 347-354.
Barbet J, Snook T, Gay J, Mealey K. ABCB1-1Δ (MDR1-1Δ) genotype is associated with adverse reaction in dogs treated with milbemycin oxime for generalized demodicosis. Journal Compilation. ESVD and ACVD 2008; 20: 111-114.
Yas-natan E, Shamir M, Kleinbart S, Aroch I. Doramectin toxicity in a collie. The Veterinary Record 2003; 153: 718-720.
Paul A, Hutchens D, Firkins L, Borgstrom M. Dermal safety study with imidacloprid/moxidectin topical solution in the ivermectin sensitive collie. Vet Parasitol 2004; 121: 718-720.
Sherman J, Paul A, Firkins L. 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: 115-119.
Hugnet C, Cadore J, Buronfosse F, Pineau X, Mathet T, Berny P. Loperamide poisoning in the dog. Vet Hum Toxicol. 1996; 38: 31-33.
Sartor L, Bentjen S, Trepanier L, Mealey K. Loperamide toxicity in a collie with the MDR1 mutation associated with ivermectin sensitivity. J. Vet Intern Med. 2004; 18: 117-118.
Mealey K, Northrup N, Bentjen S. Increased toxicity of P-glycoprotein substrate chemotherapeutic agents in a dog with the MDR1 deletion mutation associated with ivermectin sensitivity. J am Vet Med Asso. 2003; 223: 1453-1455.
Vail D. Supporting the veterinary cancer patient on chemotherapy: Neutropenia and gastrointestinal toxicity. Top Companion Anim Med. 2009; 24 (3): 122-129.
Mealey K, Fidel J, Gay J, Impellizeri J, Clifford C, Bergman P. ABCB1-1Δ polymorphism can predict hematology toxicity in dogs treated with vincristine. J. Vet Intern Med. 2008; 22: 996-1000.
Henik R, Kellum H, Bentjen S, Mealey K. Digoxin and mexiletine sensitivity in a collie with the MDR1 mutation. J Vet Intern Med. 2006; 20: 415-417.
Mealey K. Therapeutic implications of the MDR 1 –gen. J. Vet. Pharmacol. Therap. 2004; 27: 257-264.
Mealey K, Gay J, Martin L, Waiting D. Comparison of the hypothalamic-pituitary-adrenal axis in MDR1-1Δ and MDR1 wild-type dogs. Journal of Veterinary Emergency and Critical Care 2007; 17: 61-66.
Pekcec A, Schneider EL, Baumgartner W, Stein VM, Tipold A, Postchka H. Age-dependent decline of blood-brain barrier P-glycoprotein expression in the canine brain. Neurobiology of Aging 2011; 32: 1477-1485.
Mealey K. A new tool that detects ivermectin and other drugs sensitivities in dogs. Vet Med. 2004; 99: 419-426.
Kawabata A, Momoi Y, Inoue-murayama M, Iwasaki T. Canine MDR1 gene mutation in Japan. J. Vet. Med. Sci. 2005; 67: 1103-1107.
Schinkel A. P-Glycoprotein, a gatekeeper in the blood-brain barrier. Advance Drug Delivery Reviews 1999; 36: 179-194.
Fromm M. Importance of P-glycoprotein at blood-tissue barriers. TRENDS in Pharmacological Sciences 2004; 25 (8): 423-429.
Ueda K, Cardalleri C, Gottesman M, Pastan I. Expression of a full-length cDNA for the human “MDR1” gene confers resistance to colchicines, doxorubicin and vinblastine. Proc. Nalt. Acad. Sci. USA 1987; 84: 3004-3008.
Fromm M. Importance of P-glycoprotein for drug disposition in humans. European Journal of Clinical Investigation 2003; 33: 6-9.
Thiebaut F, Tsuruo T, Hamada H, Gottesman M, Pastan I, Willingham M. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sci. 1987; 84: 7735-7738.
Fromm M. P-glycoprotein: A defense mechanism limiting oral bioavailability and CNS accumulation of drugs. International Journal of Clinical Pharmacology and Therapeutics 2000; 38: 69-74.
Loscher W, Potschka H. Role of drug efllux transporters in the brain for drug disposition and treatment of brain diseases. Progress in Neurobiology 2005; 76: 22-76.
Lankas G, Wise LD, Cartwright M, Pippert T, Umbenhauer D. Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reproductive Toxicology 1998; 12 (4): 457-463.
Schrickx J, Fink-gremmels J. Implications of ABC transporters on the disposition of typical veterinary medicinal products. European Journal of Pharmacology 2008; 585: 510-519.
Geyer J, Doring B, Godoy J, Leidolf R, Moritz A, Petzinger E. Frequency of the nt230(del4) MDR1 mutation in collies and related dogs breeds in Germany. J. Vet. Pharmacol. Therap. 2005; 28: 545-551.
Dean M. The genetics of ATP-binding cassette transporters. Methods in Enzymology 2005; 400: 409-429.
Klintzsch S, Meerkamp K, Doring B, Geyer J. Detection of the nt230(del4) MDR1 mutation in dogs by a fluorogenic 5’nuclease TaqMan allelic discrimination method. The Veterinary Journal 2010; 185: 272-277.
Geyer J, Doring B, Godoy J, Moritz A, Petzinger E. Development of a PCR-based diagnostic test detecting a nt230(del4) MDR1 mutation in dogs: Verification in a moxidectin-sensitive Australian shepherd. J. Vet. Pharmacol. Therap. 2005; 28: 95-99.
Mealey K, Meurs K, Breed distribution of the ABCB1-1Δ (multidrug sensitivity) polymorphism among dogs undergoing ABCB1 genotiping. Journal of the American Veterinary Medical Association 2008; 233: 921-924.
Menez 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. Biochemical Pharmacology 2012; 83: 269-278.
Mealey K. Canine ABCB1 and macrocyclic lactones: Heartworm prevention and pharmacogenetics. Veterinary Parasitology 2008; 158: 215-222.
Lespine A, Menez C, Bourguinat C, Prichard R. P-glycoproteins and other multidrug resistance transporters in the pharmacology of anthelmintics: Prospects for reversing transport-dependent anthelmintic resistance. International Journal of Parasitology: Drugs and Drug Resistance 2011; 10: 1-18.
Hugnet C, Bentjen S, Mealey K. Frequency of the mutant MDR1 allele associated with multidrug sensitivity in a sample of collies from France. J. Vet. Pharmacol. Therap. 2004; 27: 227-229.
Mealey K, Munyard K, Bentjen S. Frequency of the mutant MDR1 allele associated with multidrug sensitivity in a sample of herding breed dogs living in Australia. Veterinary Parasitology 2005; 131: 193-196.
Roulet A, Puel O, Gesta S, Lepage J, Drag M, Soll M. et al. MDR1-deficient genotype in collie dogs hypersensitive to the P-glycoprotein substrate ivermectin. European Journal of Pharmacology 2003; 460: 85-91.
Gramer I, Leidolf R, Doring B, Klintzsch S, Kramer E, Yalcin E. et al. Breed distribution of the nt230(del4) MDR1 mutation in dogs. The Veterinary Journal 2011; 189: 67-71.
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: 727-733.
Kitamura Y, Koto H, Matsuura S, Kawabata T, Tsuchiya H, Kusuhara H. et al. Modest effect of impaired P-glycoprotein on the plasma concentration of fexofenadine, quinidine and loperamide following oral administration in collies. Drug Metabolism and Disposition 2008; 36: 807-810.
Nelson O, Carsten E, Bentjen S, Mealey K. Ivermectin toxicity in an Australian shepherd dog with the MDR1 mutation associated with ivermectin sensitivity in collies. J Vet Intern Med. 2003; 17: 354-356.
Geyer J, Klintzsch S, Meerkamp M, Wohlke A, Distl O, Moritz A. et al. Detection of the nt230(del4)MDR1 mutation in White Swiss Shepherd dogs: Case reports of doramectin toxicosis, breed predispositions, and microsatellite analysis. J. Vet. Pharmacol. Therap. 2007; 30: 482-485.
Fecht S, Wohlke A, Hamann H, Distl O. Analysis of the canine MDR1 - 1Δ mutation in the dog breed Elo. J. Vet. Med. A. 2007; 54: 401- 405.
Baars C, Leeb T, Klopmann T, Tipold A, Potschka H. Allele-specific polymerase chain reaction diagnostic test for the functional MDR1 polymorphism in dog. The Veterinary Journal 2008; 177: 394-397.
Tappin S, Goodfellow M, Peters I, Day M, Vall E, Bentjen S. et al. Frequency of the mutant MDR1 allele associated with multidrug sensitivity in dogs in the United Kingdom. In BSAVA congress, scientific proceedings, veterinary programs; 2008.
Mealey K, Bentjen S, Waiting D. Frequency of the mutant MDR1 allele associated whit ivermectin sensitivity in a sample population of collies from the northwestern United States. American Journal of Veterinary Research 2002; 63: 479-481.
Neff M, Robertson K, Wong A, Safra N, Broman K, Slatkin M. et al. Breed distribution and history of canine MDR1-1Δ, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage. PNAS 2004; 101 (32): 11725-11730.
Mealey K. Pharmacogenetics. Vet Clin Small Anim. 2006; 36: 961- 973.
Martinez M, Modric S, Sharkey M, Troutman L, Walker L, Mealey K. The pharmacogenomics of P-glycoprotein and its role in veterinary medicine. J. Vet. Pharmacol. Therap. 2008; 31: 285-300.
Sherman J. Understanding the impact of P-glycoprotein mutation on canine health. The Veterinary Journal 2011; 190: 13-14.
Coelho J, Tucker R, Mattoon J, Roberts G, Waiting D, Mealey K. Biliary excretion of technetium-99msestamibi in wild-type dogs and in dogs with intrinsic (ABCB1 -1Δ mutation) and extrinsic (ketoconazole treated) P-glycoprotein deficiency. J. Vet. Pharmacol. Therap. 2009; 32: 417-421.
Gokbulut C, Karademir U, Boyacioglu M, McKellar Q. Comparative plasma dispositions of ivermectin and doramectin following subcutaneous and oral administration in dogs. Veterinary Parasitology 2006; 135: 347-354.
Barbet J, Snook T, Gay J, Mealey K. ABCB1-1Δ (MDR1-1Δ) genotype is associated with adverse reaction in dogs treated with milbemycin oxime for generalized demodicosis. Journal Compilation. ESVD and ACVD 2008; 20: 111-114.
Yas-natan E, Shamir M, Kleinbart S, Aroch I. Doramectin toxicity in a collie. The Veterinary Record 2003; 153: 718-720.
Paul A, Hutchens D, Firkins L, Borgstrom M. Dermal safety study with imidacloprid/moxidectin topical solution in the ivermectin sensitive collie. Vet Parasitol 2004; 121: 718-720.
Sherman J, Paul A, Firkins L. 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: 115-119.
Hugnet C, Cadore J, Buronfosse F, Pineau X, Mathet T, Berny P. Loperamide poisoning in the dog. Vet Hum Toxicol. 1996; 38: 31-33.
Sartor L, Bentjen S, Trepanier L, Mealey K. Loperamide toxicity in a collie with the MDR1 mutation associated with ivermectin sensitivity. J. Vet Intern Med. 2004; 18: 117-118.
Mealey K, Northrup N, Bentjen S. Increased toxicity of P-glycoprotein substrate chemotherapeutic agents in a dog with the MDR1 deletion mutation associated with ivermectin sensitivity. J am Vet Med Asso. 2003; 223: 1453-1455.
Vail D. Supporting the veterinary cancer patient on chemotherapy: Neutropenia and gastrointestinal toxicity. Top Companion Anim Med. 2009; 24 (3): 122-129.
Mealey K, Fidel J, Gay J, Impellizeri J, Clifford C, Bergman P. ABCB1-1Δ polymorphism can predict hematology toxicity in dogs treated with vincristine. J. Vet Intern Med. 2008; 22: 996-1000.
Henik R, Kellum H, Bentjen S, Mealey K. Digoxin and mexiletine sensitivity in a collie with the MDR1 mutation. J Vet Intern Med. 2006; 20: 415-417.
Mealey K. Therapeutic implications of the MDR 1 –gen. J. Vet. Pharmacol. Therap. 2004; 27: 257-264.
Mealey K, Gay J, Martin L, Waiting D. Comparison of the hypothalamic-pituitary-adrenal axis in MDR1-1Δ and MDR1 wild-type dogs. Journal of Veterinary Emergency and Critical Care 2007; 17: 61-66.
Pekcec A, Schneider EL, Baumgartner W, Stein VM, Tipold A, Postchka H. Age-dependent decline of blood-brain barrier P-glycoprotein expression in the canine brain. Neurobiology of Aging 2011; 32: 1477-1485.
Mealey K. A new tool that detects ivermectin and other drugs sensitivities in dogs. Vet Med. 2004; 99: 419-426.
Kawabata A, Momoi Y, Inoue-murayama M, Iwasaki T. Canine MDR1 gene mutation in Japan. J. Vet. Med. Sci. 2005; 67: 1103-1107.
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