Pharmacogenetics in Veterinary Medicine: Part I
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Published:
Aug 16, 2022
Keywords:
Pharmacogenetics Veterinary Medicine Pharmacokinetics ABCB1 transporter P-glycoproteins Cytochrome P450
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Abstract
Similar to human being, animal patients vary widely in their responses to medications. Variation in drug response often causes problems in the treatment since it can result in unpredictable and variability of therapeutic efficacy and sometimes serious adverse drug reactions. One of the key factors that contributed to variation in drug responses is the genetic factors, especially genetic polymorphism of the proteins that play an important role in pharmacokinetics and pharmacodynamics. The aim of this article is to provide useful information on veterinary pharmacogenetics. In part I of the series we focused on the basic knowledge in pharmacogenetics, the different forms of variation in drug responses, and the pharmacogenetics of ABCB1 which is a member of ATP-driven drug efflux carriers. In part II of the series, we focused on the cytochrome P450 enzymes which play an important role in pharmacokinetics of drugs commonly used in veterinary medicine and the application of genetic testing in veterinary clinical practice.
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Review Article
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References
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Aithen, M. M. 1983. Species differences in pharmacodynamics: some examples. Vet. Res. Commun. 7:313-324.
Coelho, J. C., R. Tucker, J. Mattoon, G. Roberts, D. K. Waiting, and K. L. Mealey. 2009. 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. 32:417-421.
Dorrestein, G. M. and v. A. S. J. P. A. M. Miert. 1988. Pharmacotherapeutic aspects of medication of birds. J vet Pharmacol Therap. 11:33-44.
Dowling, P. M. 2015 (cited 3 November 2021) Drugs to control or stimulate vomiting (monogastric). Available from: https://www.msdvetmanual.com/pharmacology/systemic-pharmacotherapeutics-of-the-digestive-system/drugs-to-control-or-stimulate-vomiting-monogastric.
Drazen, J. M., E. K. Silverman, and T. H. Lee. 2000. Heterogeneity of therapeutic responses in asthma. Br. Med. Bull. 56(4):1054-1067.
Evans, W. E. and J. A. Johnson. 2001. Pharmacogenomics: The Inherited Basis for Interindividual Differences in Drug Response. Annu. Rev. Genomics. Hum. Genet. 2:9-39.
Evans, W. E. and H. L. McLeod. 2003. Pharmacogenomics--drug disposition, drug targets, and side effects. N. Engl. J. Med, 348(6):538-549.
Evans, W. E. and M. V. Relling. 1999. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 286(5439):487-499.
Firdova, Z., E. Turnova, M. Bielikova, J. Turna, and A. Dudas. 2016. The prevalence of ABCB1: c.227_230delATAG mutation in affected dog breeds from European countries. Res. Vet. Sci. 106:89-92.
Ginn, P. E. 1996. Immunohistochemical detection of P-glycoprotein in formalin-fixed and paraffin-embedded normal and neoplastic canine tissues. Vet. Pathol. 33(5):533-541.
Gonzales, H. M., J. W. McGillicuddy, V. Rohan, J. L. Chandler, S. N. Nadig, D. A. Dubay, and D. J. Taber. 2020. A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation. Am. J. Transplant. 20(8):1969-1983.
Gustafson, D. L. and D. H. Thamm. 2010. Pharmacokinetic modeling of doxorubicin pharmacokinetics in dogs deficient in ABCB1 drug transporters. J. Vet. Intern. Med. 24(3):579-586.
Ingelman-Sundberg, M. 2001. Pharmacogenetics: an opportunity for a safer and more efficient pharmacotherapy. J. Intern. Med. 250(3):186-198.
Kamata, M., S. Nagahama, K. Kakishima, N. Sasaki, and R. Nishimura. 2012. Comparison of Behavioral Effects of Morphine and Fentanyl in Dogs and Cats. J. Vet. Med. Sci. 74(2):231–234.
Kiso, S., S. H. Cai, K. Kitaichi, N. Furui, K. Takagi, K. Takagi, T. Nabeshima, T. Hasegawa, and S. Kiso. 2000. Inhibitory effect of erythromycin on P-glycoprotein mediated biliary excretion of doxorubicin in rats. Anticancer Res. 20:2827-2834.
Kuypers D. R. 2020. Intra-patient variability of tacrolimus exposure in solid organ transplantation: a novel marker for clinical outcome. Clin. Pharmacol. Ther. 107(2):347-358.
Maitland, v. d. Z. A., A. de Boer, and H. Leufkens. 2000. The interface between pharmacoepidemiology and pharmacogenetics. Eur. J. Pharmacol. 410(2):121-134.
Malki, M. A., and E. R. Pearson. 2020. Drug–drug–gene interactions and adverse drug reactions. Pharmacogenomics J. 20:355–366.
Mancinelli, L., M. Cronin, and W. Sadée. 2000. Pharmacogenomics: the promise of personalized medicine. AAPS Pharm. Sci. 2(1):4-9.
Marelli, S. P., M. Polli, S. Frattini, M. Cortellari, R. Rizzi, and P. Crepaldi. 2020. Genotypic and allelic frequencies of MDR1 gene in dogs in Italy. Vet. Rec. Open. 7(1):e000375.
Martinez, M., S. Modric, M. Sharkey, L. Troutman, L. Walker, and K. Mealey. 2008. The pharmacogenomics of P-glycoprotein and its role in veterinary medicine. J. Vet. Pharmacol. Ther. 31:285-300.
McLean, M. K. and S. A. Khan. 2018. Toxicology of frequently encountered nonsteroidal anti-inflammatory drugs in dogs and cats. An update. Vet. Clin. North Am. Small Anim. Pract. 48(6):969-984.
Mealey, K. L., S. A. Bentjen, J. M. Gay, and G. H. Cantor. 2001. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics J. 11:727-733.
Mealey, K. L., J. Fidel, J.M. Gay, J.A. Impellizeri, C.A. Clifford, and P.J. Bergman. 2008. ABCB1-1Delta polymorphism can predict hematologic toxicity in dogs treated with vincristine. J. Vet. Intern. Med. 22:996-1000.
Mealey, K. L., S. Greene, R. Bagley, J. Gay, R. Tucker, P. Gavin, K. Schmidt, and F. Nelson. 2008. P-glycoprotein contributes to the blood-brain, but not blood-cerebrospinal fluid, barrier in a spontaneous canine p-glycoprotein knockout model. Drug Metab. Dispos. 36(6):1073-1079.
Mealey, K. L., S. E. Martinez, N. F. Villarino, and M. H. Court. 2019. Personalized medicine: going to the dogs? Hum. Genet. 138:467–481.
Mealey, K. L. and K. M. Meurs. 2008. Breed distribution of the ABCB1-1Delta (multidrug sensitivity) polymorphism among dogs undergoing ABCB1 genotyping. J. Am. Vet. Med. Assoc. 233:921-924.
Merola, V. M. and P. A. Eubig. 2018. Toxicology of avermectins and milbemycins (macrocyclic lactones) and the role of P-glycoprotein in dogs and cats. Vet. Clin. North Am. Small Anim. Pract. 48(6):991-1012.
Micaglio, E., E. T. Locati, M. M. Monasky, F. Romani, F. Heilbron, and C. Pappone. 2021. Role of pharmacogenetics in adverse drug reactions: an update towards personalized medicine. Front. Pharmacol. 12:1-17.
Mosher, C. M. and M. H. Court. 2010. Pharmacogenomics. In: Cunningham F., J. Elliott, P. Lees. editors. Comparative and veterinary pharmacology (handbook of experimental pharmacology 199) 2010th ed. Springer, New York. p49-77.
Neff, M. W., K. R. Robertson, A. K. Wong, N. Safra, K. W. Broman, M. Slatkin, K. L. Mealey, and N. C. Pedersen. 2004. 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. 101(32):11725-11730.
Paul, A. J., W. J. Tranquilli, R. L. Seward, K. S. Jr. Todd, and J. A. DiPietro. 1987. Clinical observations in collies given ivermectin orally. Am. J. Vet. Res. 48(4 ):684–685.
Pilar, G., R. Nunez, I. McLennan, and S. D. Meriney. 1987. Muscarinic and nicotinic synaptic activation of the developing chicken iris. J. Neurosci, 7:3813–3826.
Posner, L. P. 2018. Anesthetics and analgesics, and drugs acting on the central nervous system. In: J. E. Riviere & M. G. Papich, editors, Veterinary pharmacology and therapeutics. 10th ed. Wiley-Blackwell, New York. p. 253-276
Pulliam J. D. and J. M. Preston. 1989. Safety of ivermectin in target animals. In: W. A. Campbell, editor. Ivermectin and Abamectin. 1st ed. Springer, New York. P. 149–161.
Russell, L. E., Y. Zhou, A. A. Almousa, J. K. Sodhi, C. K. Nwabufo, and V. M. Lauschke. 2021. Pharmacogenomics in the era of next generation sequencing – from byte to bedside. Drug Metab. Rev. 53(2):253-278.
Sartor L. L., S. A. Bentjen, L. Trepanier, and K. L. Mealey. 2004. Loperamide toxicity in a collie with the MDR1 mutation associated with ivermectin sensitivity. J. Vet. Intern. Med. 18(1):117-8.
Song, S., H. Suzuki, R. Kawai, and Y. Sugiyama. 1999. Effect of PSC 833, a P-glycoprotein modulator, on the disposition of vincristine and digoxin in rats. Drug Metab. Dispos. 27:689-694.
Toutain, P. L., A. Ferran, and A. Bousquet-Mélou. 2010. Species differences in pharmacokinetics and pharmacodynamics. In: F. Cunningham, J. Elliott and P. Lees, editors, Comparative and Veterinary Pharmacology. Handbook of Experimental Pharmacology. Springer, Berlin, Heidelberg. p. 199-257.
Tranquilli W. J., A. J. Paul, R. L. Seward, K. S. Todd, and J. A. DiPietro. 1987. Response to physostigmine administration in collie dogs exhibiting ivermectin toxicosis. J. Vet. Pharmacol. Ther. 10(1):96–100.
Vesell, E. S. 1997. Therapeutic lessons from pharmacogenetics. Ann. Intern. Med. 126(8):653-665.
Viviano, K. R. 2019. Pharmacotherapeutics of cancer. In: K. L. Mealey, editor, Pharmacotherapeutics for veterinary dispensing. 1st ed. John Wiley & Sons Inc, New Jersey, P. 453-469.
Wandel, C., R. Kim, M. Wood, and A. Wood. 2002. Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology. 96:913-920.
Wang, L., H. L. McLeod, and R. M. Weinshilboum. 2011. Genomics and drug response. N. Engl. J. Med. 364(12):1144-1153.
Wang, Y. T., M. Y. Merl, J. Yang, Z. X. Zhu, and G. H. Li. 2020. Opportunities for pharmacists to integrate pharmacogenomics into clinical practice. Pharmacogenomics J. 20:169–178.
WSU Veterinary Clinical Pharmacology Laboratory, 2021. (cited 13 November 2021) Affected Breeds. Available from: https://vcpl.vetmed.wsu.edu/affected-breeds
Aithen, M. M. 1983. Species differences in pharmacodynamics: some examples. Vet. Res. Commun. 7:313-324.
Coelho, J. C., R. Tucker, J. Mattoon, G. Roberts, D. K. Waiting, and K. L. Mealey. 2009. 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. 32:417-421.
Dorrestein, G. M. and v. A. S. J. P. A. M. Miert. 1988. Pharmacotherapeutic aspects of medication of birds. J vet Pharmacol Therap. 11:33-44.
Dowling, P. M. 2015 (cited 3 November 2021) Drugs to control or stimulate vomiting (monogastric). Available from: https://www.msdvetmanual.com/pharmacology/systemic-pharmacotherapeutics-of-the-digestive-system/drugs-to-control-or-stimulate-vomiting-monogastric.
Drazen, J. M., E. K. Silverman, and T. H. Lee. 2000. Heterogeneity of therapeutic responses in asthma. Br. Med. Bull. 56(4):1054-1067.
Evans, W. E. and J. A. Johnson. 2001. Pharmacogenomics: The Inherited Basis for Interindividual Differences in Drug Response. Annu. Rev. Genomics. Hum. Genet. 2:9-39.
Evans, W. E. and H. L. McLeod. 2003. Pharmacogenomics--drug disposition, drug targets, and side effects. N. Engl. J. Med, 348(6):538-549.
Evans, W. E. and M. V. Relling. 1999. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 286(5439):487-499.
Firdova, Z., E. Turnova, M. Bielikova, J. Turna, and A. Dudas. 2016. The prevalence of ABCB1: c.227_230delATAG mutation in affected dog breeds from European countries. Res. Vet. Sci. 106:89-92.
Ginn, P. E. 1996. Immunohistochemical detection of P-glycoprotein in formalin-fixed and paraffin-embedded normal and neoplastic canine tissues. Vet. Pathol. 33(5):533-541.
Gonzales, H. M., J. W. McGillicuddy, V. Rohan, J. L. Chandler, S. N. Nadig, D. A. Dubay, and D. J. Taber. 2020. A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation. Am. J. Transplant. 20(8):1969-1983.
Gustafson, D. L. and D. H. Thamm. 2010. Pharmacokinetic modeling of doxorubicin pharmacokinetics in dogs deficient in ABCB1 drug transporters. J. Vet. Intern. Med. 24(3):579-586.
Ingelman-Sundberg, M. 2001. Pharmacogenetics: an opportunity for a safer and more efficient pharmacotherapy. J. Intern. Med. 250(3):186-198.
Kamata, M., S. Nagahama, K. Kakishima, N. Sasaki, and R. Nishimura. 2012. Comparison of Behavioral Effects of Morphine and Fentanyl in Dogs and Cats. J. Vet. Med. Sci. 74(2):231–234.
Kiso, S., S. H. Cai, K. Kitaichi, N. Furui, K. Takagi, K. Takagi, T. Nabeshima, T. Hasegawa, and S. Kiso. 2000. Inhibitory effect of erythromycin on P-glycoprotein mediated biliary excretion of doxorubicin in rats. Anticancer Res. 20:2827-2834.
Kuypers D. R. 2020. Intra-patient variability of tacrolimus exposure in solid organ transplantation: a novel marker for clinical outcome. Clin. Pharmacol. Ther. 107(2):347-358.
Maitland, v. d. Z. A., A. de Boer, and H. Leufkens. 2000. The interface between pharmacoepidemiology and pharmacogenetics. Eur. J. Pharmacol. 410(2):121-134.
Malki, M. A., and E. R. Pearson. 2020. Drug–drug–gene interactions and adverse drug reactions. Pharmacogenomics J. 20:355–366.
Mancinelli, L., M. Cronin, and W. Sadée. 2000. Pharmacogenomics: the promise of personalized medicine. AAPS Pharm. Sci. 2(1):4-9.
Marelli, S. P., M. Polli, S. Frattini, M. Cortellari, R. Rizzi, and P. Crepaldi. 2020. Genotypic and allelic frequencies of MDR1 gene in dogs in Italy. Vet. Rec. Open. 7(1):e000375.
Martinez, M., S. Modric, M. Sharkey, L. Troutman, L. Walker, and K. Mealey. 2008. The pharmacogenomics of P-glycoprotein and its role in veterinary medicine. J. Vet. Pharmacol. Ther. 31:285-300.
McLean, M. K. and S. A. Khan. 2018. Toxicology of frequently encountered nonsteroidal anti-inflammatory drugs in dogs and cats. An update. Vet. Clin. North Am. Small Anim. Pract. 48(6):969-984.
Mealey, K. L., S. A. Bentjen, J. M. Gay, and G. H. Cantor. 2001. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics J. 11:727-733.
Mealey, K. L., J. Fidel, J.M. Gay, J.A. Impellizeri, C.A. Clifford, and P.J. Bergman. 2008. ABCB1-1Delta polymorphism can predict hematologic toxicity in dogs treated with vincristine. J. Vet. Intern. Med. 22:996-1000.
Mealey, K. L., S. Greene, R. Bagley, J. Gay, R. Tucker, P. Gavin, K. Schmidt, and F. Nelson. 2008. P-glycoprotein contributes to the blood-brain, but not blood-cerebrospinal fluid, barrier in a spontaneous canine p-glycoprotein knockout model. Drug Metab. Dispos. 36(6):1073-1079.
Mealey, K. L., S. E. Martinez, N. F. Villarino, and M. H. Court. 2019. Personalized medicine: going to the dogs? Hum. Genet. 138:467–481.
Mealey, K. L. and K. M. Meurs. 2008. Breed distribution of the ABCB1-1Delta (multidrug sensitivity) polymorphism among dogs undergoing ABCB1 genotyping. J. Am. Vet. Med. Assoc. 233:921-924.
Merola, V. M. and P. A. Eubig. 2018. Toxicology of avermectins and milbemycins (macrocyclic lactones) and the role of P-glycoprotein in dogs and cats. Vet. Clin. North Am. Small Anim. Pract. 48(6):991-1012.
Micaglio, E., E. T. Locati, M. M. Monasky, F. Romani, F. Heilbron, and C. Pappone. 2021. Role of pharmacogenetics in adverse drug reactions: an update towards personalized medicine. Front. Pharmacol. 12:1-17.
Mosher, C. M. and M. H. Court. 2010. Pharmacogenomics. In: Cunningham F., J. Elliott, P. Lees. editors. Comparative and veterinary pharmacology (handbook of experimental pharmacology 199) 2010th ed. Springer, New York. p49-77.
Neff, M. W., K. R. Robertson, A. K. Wong, N. Safra, K. W. Broman, M. Slatkin, K. L. Mealey, and N. C. Pedersen. 2004. 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. 101(32):11725-11730.
Paul, A. J., W. J. Tranquilli, R. L. Seward, K. S. Jr. Todd, and J. A. DiPietro. 1987. Clinical observations in collies given ivermectin orally. Am. J. Vet. Res. 48(4 ):684–685.
Pilar, G., R. Nunez, I. McLennan, and S. D. Meriney. 1987. Muscarinic and nicotinic synaptic activation of the developing chicken iris. J. Neurosci, 7:3813–3826.
Posner, L. P. 2018. Anesthetics and analgesics, and drugs acting on the central nervous system. In: J. E. Riviere & M. G. Papich, editors, Veterinary pharmacology and therapeutics. 10th ed. Wiley-Blackwell, New York. p. 253-276
Pulliam J. D. and J. M. Preston. 1989. Safety of ivermectin in target animals. In: W. A. Campbell, editor. Ivermectin and Abamectin. 1st ed. Springer, New York. P. 149–161.
Russell, L. E., Y. Zhou, A. A. Almousa, J. K. Sodhi, C. K. Nwabufo, and V. M. Lauschke. 2021. Pharmacogenomics in the era of next generation sequencing – from byte to bedside. Drug Metab. Rev. 53(2):253-278.
Sartor L. L., S. A. Bentjen, L. Trepanier, and K. L. Mealey. 2004. Loperamide toxicity in a collie with the MDR1 mutation associated with ivermectin sensitivity. J. Vet. Intern. Med. 18(1):117-8.
Song, S., H. Suzuki, R. Kawai, and Y. Sugiyama. 1999. Effect of PSC 833, a P-glycoprotein modulator, on the disposition of vincristine and digoxin in rats. Drug Metab. Dispos. 27:689-694.
Toutain, P. L., A. Ferran, and A. Bousquet-Mélou. 2010. Species differences in pharmacokinetics and pharmacodynamics. In: F. Cunningham, J. Elliott and P. Lees, editors, Comparative and Veterinary Pharmacology. Handbook of Experimental Pharmacology. Springer, Berlin, Heidelberg. p. 199-257.
Tranquilli W. J., A. J. Paul, R. L. Seward, K. S. Todd, and J. A. DiPietro. 1987. Response to physostigmine administration in collie dogs exhibiting ivermectin toxicosis. J. Vet. Pharmacol. Ther. 10(1):96–100.
Vesell, E. S. 1997. Therapeutic lessons from pharmacogenetics. Ann. Intern. Med. 126(8):653-665.
Viviano, K. R. 2019. Pharmacotherapeutics of cancer. In: K. L. Mealey, editor, Pharmacotherapeutics for veterinary dispensing. 1st ed. John Wiley & Sons Inc, New Jersey, P. 453-469.
Wandel, C., R. Kim, M. Wood, and A. Wood. 2002. Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology. 96:913-920.
Wang, L., H. L. McLeod, and R. M. Weinshilboum. 2011. Genomics and drug response. N. Engl. J. Med. 364(12):1144-1153.
Wang, Y. T., M. Y. Merl, J. Yang, Z. X. Zhu, and G. H. Li. 2020. Opportunities for pharmacists to integrate pharmacogenomics into clinical practice. Pharmacogenomics J. 20:169–178.
WSU Veterinary Clinical Pharmacology Laboratory, 2021. (cited 13 November 2021) Affected Breeds. Available from: https://vcpl.vetmed.wsu.edu/affected-breeds