• 1. Viviano KR. Update on immunosuppressive therapies for dogs and cats. Vet Clin North Am Small Anim Pract 2013;43:11491170.

  • 2. Wagner M, Earley AK, Webster AC, et al. Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2015;12:CD007746.

    • Search Google Scholar
    • Export Citation
  • 3. Kyles AE, Gregory CR, Craigmill AL. Comparison of the in vitro antiproliferative effects of five immunosuppressive drugs on lymphocytes in whole blood from cats. Am J Vet Res 2000;61:906909.

    • Search Google Scholar
    • Export Citation
  • 4. Lange S, Mueller SC, Altmann S, et al. Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2008;41:667674.

    • Search Google Scholar
    • Export Citation
  • 5. Bacek LM, Macintire DK. Treatment of primary immune-mediated hemolytic anemia with mycophenolate mofetil in two cats. J Vet Emerg Crit Care (San Antonio) 2011;21:4549.

    • Search Google Scholar
    • Export Citation
  • 6. West LD, Hart JR. Treatment of idiopathic immune-mediated hemolytic anemia with mycophenolate mofetil in five dogs. J Vet Emerg Crit Care (San Antonio) 2014;24:226231.

    • Search Google Scholar
    • Export Citation
  • 7. Abd Rahman AN, Tett SE, Staatz CE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease. Clin Pharmacokinet 2013;52:303331.

    • Search Google Scholar
    • Export Citation
  • 8. Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 1998;34:429455.

  • 9. Santamaria P. Effector lymphocytes in autoimmunity. Curr Opin Immunol 2001;13:663669.

  • 10. Devarajan P, Chen Z. Autoimmune effector memory T cells: the bad and the good. Immunol Res 2013;57:1222.

  • 11. Court MH. Feline drug metabolism and disposition: pharmacokinetic evidence for species differences and molecular mechanisms. Vet Clin North Am Small Anim Pract 2013;43:10391054.

    • Search Google Scholar
    • Export Citation
  • 12. Slovak JE, Mealey K, Court MH. Comparative metabolism of mycophenolic acid by glucuronic acid and glucose conjugation in human, dog, and cat liver microsomes. J Vet Pharmacol Ther 2017;40:123129.

    • Search Google Scholar
    • Export Citation
  • 13. Slovak JE, Rivera SM, Hwang JK, et al. Pharmacokinetics of mycophenolic acid after intravenous administration of mycophenolate mofetil to healthy cats. J Vet Intern Med 2017;31:18271832.

    • Search Google Scholar
    • Export Citation
  • 14. Slovak JE, Villarino NF. Safety of oral and intravenous mycophenolate mofetil in healthy cats. J Feline Med Surg 2018;20:184188.

  • 15. Wang A, Smith JR, Creevy KE. Treatment of canine idiopathic immune-mediated haemolytic anaemia with mycophenolate mofetil and glucocorticoids: 30 cases (2007 to 2011). J Small Anim Pract 2013;54:399404.

    • Search Google Scholar
    • Export Citation
  • 16. Rivera Vélez SM, Morassi A, Court MH, et al. Development and validation of an ultrafast chromatographic method for quantification of the immunosuppressant mycophenolic acid in canine, feline and human plasma. J Pharm Biomed Anal 2016;131:94102.

    • Search Google Scholar
    • Export Citation
  • 17. Rivera Vélez SM, Hwang JK, Slovak JE, et al. Simultaneous determination of mycophenolic acid and its glucuronide and glycoside derivatives in canine and feline plasma by UHPLC-UV. Biomed Chromatogr 2017;31:19.

    • Search Google Scholar
    • Export Citation
  • 18. US Department of Health and Human Services, FDA, Center for Drug Evaluation and Research, Center for Veterinary Medicine. Bioanalytical method validation: guidance for industry. May 2001. Available at: www.fda.gov/downloads/Drugs/Guidance. Accessed May 12, 2017.

    • Search Google Scholar
    • Export Citation
  • 19. Strober W. Trypan blue exclusion test of cell viability. Curr Protoc Immunol 2015;111:A3.B.1A3.B.3.

  • 20. Yoshimura K, Yano I, Yamamoto T, et al. Population pharmacokinetics and pharmacodynamics of mycophenolic acid using the prospective data in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 2018;53:4451.

    • Search Google Scholar
    • Export Citation
  • 21. Bravo Soto JA, Esteban de la Rosa RJ, Luna del Castillo JD, et al. Effect of mycophenolate mofetil regimen on peripheral blood lymphocyte subsets in kidney transplant recipients. Transplant Proc 2003;35:13551359.

    • Search Google Scholar
    • Export Citation
  • 22. Bremm M, Huenecke S, Zimmermann O, et al. In-vitro influence of mycophenolate mofetil (MMF) and ciclosporin A (CsA) on cytokine induced killer (CIK) cell immunotherapy. J Transl Med 2016;14:112.

    • Search Google Scholar
    • Export Citation
  • 23. Iwaszkiewicz-Grzes D, Cholewinski G, Kot-Wasik A, et al. Investigations on the immunosuppressive activity of derivatives of mycophenolic acid in immature dendritic cells. Int Immunopharmacol 2017;44:137142.

    • Search Google Scholar
    • Export Citation
  • 24. Dipchand AI, Pietra B, McCrindle BW, et al. Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil. J Heart Lung Transplant 2001;20:10351043.

    • Search Google Scholar
    • Export Citation
  • 25. Gajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: does the MPA level matter? Am J Transplant 2004;4:14951500.

    • Search Google Scholar
    • Export Citation
  • 26. Allison AC. Immunosuppressive drugs: the first 50 years and a glance forward. Immunopharmacology 2000;47:6383.

  • 27. Nowak I, Shaw LM. Mycophenolic acid binding to human serum albumin: characterization and relation to pharmacodynamics. Clin Chem 1995;41:10111017.

    • Search Google Scholar
    • Export Citation

Advertisement

Pharmacokinetics and pharmacodynamics of mycophenolic acid in healthy cats after twice-daily intravenous infusion of mycophenolate mofetil for three days

View More View Less
  • 1 Program in Individualized Medicine, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164.
  • | 2 Program in Individualized Medicine, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164.
  • | 3 Program in Individualized Medicine, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164.
  • | 4 Program in Individualized Medicine, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164.

Abstract

OBJECTIVE To evaluate the plasma disposition of mycophenolic acid (MPA) and its derivatives MPA glucuronide and MPA glucoside after twice-daily infusions of mycophenolate mofetil (MMF) in healthy cats for 3 days and to assess the effect of MMF administration on peripheral blood mononuclear cell (PBMC) counts and CD4+-to-CD8+ ratios.

ANIMALS 5 healthy adult cats.

PROCEDURES MMF was administered to each cat (10 mg/kg, IV, q 12 h for 3 days). Each dose of MMF was diluted with 5% dextrose in water and then administered over a 2-hour period with a syringe pump. Blood samples were collected for analysis. A chromatographic method was used to quantitate concentrations of MPA and its metabolites. Effects of MMF on PBMC counts and CD4+-to-CD8+ ratios were assessed by use of flow cytometry.

RESULTS All cats biotransformed MMF into MPA. The MPA area under the plasma concentration–time curve from 0 to 14 hours ranged from 14.6 to 37.6 mg·h/L and from 14.4 to 22.3 mg·h/L after the first and last infusion, respectively. Total number of PBMCs was reduced in 4 of 5 cats (mean ± SD reduction, 25.9 ± 15.8% and 26.7 ± 19.3%) at 24 and 48 hours after the end of the first infusion of MMF, respectively.

CONCLUSIONS AND CLINICAL RELEVANCE Plasma disposition of MPA after twice-daily IV infusions for 3 days was variable in all cats. There were no remarkable changes in PBMC counts and CD4+-to-CD8+ ratios.

Contributor Notes

Address correspondence to Dr. Villarino (nicolas.villarino@wsu.edu).