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Pharmacology of cyclosporine and tacrolimus

Authors
Karen Hardinger, PharmD, BCPS
Colm C Magee, MD, MPH, FRCPI
Section Editors
Daniel E Furst, MD
Daniel C Brennan, MD, FACP
Deputy Editor
Albert Q Lam, MD

INTRODUCTION

Cyclosporine and tacrolimus selectively inhibit calcineurin, thereby impairing the transcription of interleukin (IL)-2 and several other cytokines in T lymphocytes. Calcineurin inhibitors have been mainstays of immunosuppression in solid organ transplantation for over three decades.

Cyclosporine and tacrolimus are occasionally used in the treatment of various immune-mediated diseases. However, concerns about their long-term toxicity (especially renal dysfunction and hypertension) and the availability of newer biologic agents have restricted the use of cyclosporine and tacrolimus to patients who have not responded to conventional treatment. The renal toxicity of these agents is reviewed in detail separately. (See "Cyclosporine and tacrolimus nephrotoxicity".)

The pharmacology of cyclosporine and tacrolimus is reviewed here. The efficacy and use of these agents in specific conditions, including organ transplantation and immune-mediated diseases, are discussed separately in the topic reviews addressing the treatment of each disorder. (See appropriate topic reviews.)

MECHANISM OF ACTION

Cyclosporine is a lipophilic cyclic peptide of 11 amino acids, while tacrolimus is a macrolide antibiotic. Both drugs have been isolated from fungi and possess similar suppressive effects on cell-mediated and humoral immune responses.

Both drugs bind with high affinity to a family of cytoplasmic proteins present in most cells: cyclophilins for cyclosporine, and FK-binding proteins for tacrolimus. The drug-receptor complex specifically and competitively binds to and inhibits calcineurin, a calcium- and calmodulin-dependent phosphatase [1-4]. This process inhibits the translocation of a family of transcription factors (NF-AT), leading to reduced transcriptional activation of cytokine genes for interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, IL-3, IL-4, CD40L, granulocyte-macrophage colony-stimulating factor, and interferon-gamma [1,2,5,6]. Ultimately, proliferation of T lymphocytes is reduced.

                               

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Literature review current through: Nov 2016. | This topic last updated: Wed Oct 12 00:00:00 GMT+00:00 2016.
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References
Top
  1. Wiederrecht G, Lam E, Hung S, et al. The mechanism of action of FK-506 and cyclosporin A. Ann N Y Acad Sci 1993; 696:9.
  2. Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Immunol Today 1992; 13:136.
  3. Kahan BD. Cyclosporine. N Engl J Med 1989; 321:1725.
  4. Klintmalm GB. FK 506: an update. Clin Transplant 1994; 8:207.
  5. Mochizuki M, Masuda K, Sakane T, et al. A clinical trial of FK506 in refractory uveitis. Am J Ophthalmol 1993; 115:763.
  6. Jegasothy BV, Ackerman CD, Todo S, et al. Tacrolimus (FK 506)--a new therapeutic agent for severe recalcitrant psoriasis. Arch Dermatol 1992; 128:781.
  7. Shin GT, Khanna A, Ding R, et al. In vivo expression of transforming growth factor-beta1 in humans: stimulation by cyclosporine. Transplantation 1998; 65:313.
  8. Slattery C, Campbell E, McMorrow T, Ryan MP. Cyclosporine A-induced renal fibrosis: a role for epithelial-mesenchymal transition. Am J Pathol 2005; 167:395.
  9. Ishida Y, Matsuda H, Kida K. Effect of cyclosporin A on human bone marrow granulocyte-macrophage progenitors with anti-cancer agents. Acta Paediatr Jpn 1995; 37:610.
  10. Spence MM, Nguyen LM, Hui RL, Chan J. Evaluation of clinical and safety outcomes associated with conversion from brand-name to generic tacrolimus in transplant recipients enrolled in an integrated health care system. Pharmacotherapy 2012; 32:981.
  11. Cabello M, García P, González-Molina M, et al. Pharmacokinetics of once- versus twice-daily tacrolimus formulations in kidney transplant patients receiving expanded criteria deceased donor organs: a single-center, randomized study. Transplant Proc 2010; 42:3038.
  12. http://www.veloxis.com/technology/cfm (Accessed on April 18, 2016).
  13. Astagraf XL prescribing information 12/2015. http://www.astellas.us/docs/AstagrafXL.pdf (Accessed on April 13, 2016).
  14. Pennington CA, Park JM. Sublingual tacrolimus as an alternative to oral administration for solid organ transplant recipients. Am J Health Syst Pharm 2015; 72:277.
  15. Astellas. ASTAGRAF XL. Effects of ethanol on the dissolution properties of tacrolimus extended-release study No. PCAR1301280. Data on file.
  16. Kamar N, Garrigue V, Karras A, et al. Impact of early or delayed cyclosporine on delayed graft function in renal transplant recipients: a randomized, multicenter study. Am J Transplant 2006; 6:1042.
  17. Lebranchu Y, Bridoux F, Büchler M, et al. Immunoprophylaxis with basiliximab compared with antithymocyte globulin in renal transplant patients receiving MMF-containing triple therapy. Am J Transplant 2002; 2:48.
  18. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3:S1.
  19. Prograf prescribing information 5/2015. http://www.astellas.us/docs/prograf.pdf (Accessed on April 13, 2016).
  20. Levy G, Thervet E, Lake J, et al. Patient management by Neoral C(2) monitoring: an international consensus statement. Transplantation 2002; 73:S12.
  21. Thervet E, Pfeffer P, Scolari MP, et al. Clinical outcomes during the first three months posttransplant in renal allograft recipients managed by C2 monitoring of cyclosporine microemulsion. Transplantation 2003; 76:903.
  22. Cole E, Maham N, Cardella C, et al. Clinical benefits of neoral C2 monitoring in the long-term management of renal transplant recipients. Transplantation 2003; 75:2086.
  23. Cantarovich M, Barkun JS, Tchervenkov JI, et al. Comparison of neoral dose monitoring with cyclosporine through levels versus 2-hr postdose levels in stable liver transplant patients. Transplantation 1998; 66:1621.
  24. Anglicheau D, Verstuyft C, Laurent-Puig P, et al. Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. J Am Soc Nephrol 2003; 14:1889.
  25. Thervet E, Anglicheau D, King B, et al. Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation 2003; 76:1233.
  26. Tsuchiya N, Satoh S, Tada H, et al. Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation 2004; 78:1182.
  27. Gervasini G, Garcia M, Macias RM, et al. Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation. Transpl Int 2012; 25:471.
  28. Singh R, Srivastava A, Kapoor R, Mittal RD. Do drug transporter (ABCB1) SNPs influence cyclosporine and tacrolimus dose requirements and renal allograft outcome in the posttransplantation period? J Clin Pharmacol 2011; 51:603.
  29. Pallet N, Etienne I, Buchler M, et al. Long-Term Clinical Impact of Adaptation of Initial Tacrolimus Dosing to CYP3A5 Genotype. Am J Transplant 2016; 16:2670.
  30. Alloway R, Steinberg S, Khalil K, et al. Conversion of stable kidney transplant recipients from a twice daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc 2005; 37:867.
  31. van Hooff J, Van der Walt I, Kallmeyer J, et al. Pharmacokinetics in stable kidney transplant recipients after conversion from twice-daily to once-daily tacrolimus formulations. Ther Drug Monit 2012; 34:46.
  32. Florman S, Alloway R, Kalayoglu M, et al. Conversion of stable liver transplant recipients from a twice-daily Prograf-based regimen to a once-daily modified release tacrolimus-based regimen. Transplant Proc 2005; 37:1211.
  33. Zhang YF, Chen XY, Dai XJ, et al. Pharmacokinetics of tacrolimus converted from twice-daily formulation to once-daily formulation in Chinese stable liver transplant recipients. Acta Pharmacol Sin 2011; 32:1419.
  34. Heffron TG, Pescovitz MD, Florman S, et al. Once-daily tacrolimus extended-release formulation: 1-year post-conversion in stable pediatric liver transplant recipients. Am J Transplant 2007; 7:1609.
  35. Alloway R, Vanhaecke J, Yonan N, et al. Pharmacokinetics in stable heart transplant recipients after conversion from twice-daily to once-daily tacrolimus formulations. J Heart Lung Transplant 2011; 30:1003.
  36. Envarsus XR prescribing information 6/2015 http:www/envarsusxr.com/files/1814/4899/3398/EnvarsusXR_PI_8_4_15.pdf (Accessed on April 13, 2016).
  37. Doligalski CT, Liu EC, Sammons CM, et al. Sublingual administration of tacrolimus: current trends and available evidence. Pharmacotherapy 2014; 34:1209.
  38. Kolars JC, Awni WM, Merion RM, Watkins PB. First-pass metabolism of cyclosporin by the gut. Lancet 1991; 338:1488.
  39. Hooks MA. Tacrolimus, a new immunosuppressant--a review of the literature. Ann Pharmacother 1994; 28:501.
  40. Mancinelli LM, Frassetto L, Floren LC, et al. The pharmacokinetics and metabolic disposition of tacrolimus: a comparison across ethnic groups. Clin Pharmacol Ther 2001; 69:24.
  41. Bekersky I, Dressler D, Mekki Q. Effect of time of meal consumption on bioavailability of a single oral 5 mg tacrolimus dose. J Clin Pharmacol 2001; 41:289.
  42. Small DS, Acheampong A, Reis B, et al. Blood concentrations of cyclosporin a during long-term treatment with cyclosporin a ophthalmic emulsions in patients with moderate to severe dry eye disease. J Ocul Pharmacol Ther 2002; 18:411.
  43. Olson KA, West K, McCarthy PL. Toxic tacrolimus levels after application of topical tacrolimus and use of occlusive dressings in two bone marrow transplant recipients with cutaneous graft-versus-host disease. Pharmacotherapy 2014; 34:e60.
  44. Bramham K, Chusney G, Lee J, et al. Breastfeeding and tacrolimus: serial monitoring in breast-fed and bottle-fed infants. Clin J Am Soc Nephrol 2013; 8:563.
  45. Iwasaki K, Shiraga T, Matsuda H, et al. Further metabolism of FK506 (tacrolimus). Identification and biological activities of the metabolites oxidized at multiple sites of FK506. Drug Metab Dispos 1995; 23:28.
  46. Jusko WJ, Piekoszewski W, Klintmalm GB, et al. Pharmacokinetics of tacrolimus in liver transplant patients. Clin Pharmacol Ther 1995; 57:281.
  47. Chisholm MA, Mulloy LL, Jagadeesan M, DiPiro JT. Coadministration of tacrolimus with anti-acid drugs. Transplantation 2003; 76:665.
  48. Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. Clin Pharmacokinet 2010; 49:141.
  49. Ejendal KF, Hrycyna CA. Differential sensitivities of the human ATP-binding cassette transporters ABCG2 and P-glycoprotein to cyclosporin A. Mol Pharmacol 2005; 67:902.
  50. Saitoh H, Saikachi Y, Kobayashi M, et al. Limited interaction between tacrolimus and P-glycoprotein in the rat small intestine. Eur J Pharm Sci 2006; 28:34.
  51. Amioka K, Kuzuya T, Kushihara H, et al. Carvedilol increases ciclosporin bioavailability by inhibiting P-glycoprotein-mediated transport. J Pharm Pharmacol 2007; 59:1383.
  52. Hoorn EJ, Walsh SB, McCormick JA, et al. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nat Med 2011; 17:1304.
  53. Schwartz RB, Bravo SM, Klufas RA, et al. Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy: CT and MR findings in 16 cases. AJR Am J Roentgenol 1995; 165:627.
  54. Eidelman BH, Abu-Elmagd K, Wilson J, et al. Neurologic complications of FK 506. Transplant Proc 1991; 23:3175.
  55. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group. Lancet 1994; 344:423.
  56. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. The U.S. Multicenter FK506 Liver Study Group. N Engl J Med 1994; 331:1110.
  57. Wijdicks EF, Wiesner RH, Krom RA. Neurotoxicity in liver transplant recipients with cyclosporine immunosuppression. Neurology 1995; 45:1962.
  58. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996; 334:494.
  59. Prommer E. Calcineurin-inhibitor pain syndrome. Clin J Pain 2012; 28:556.
  60. Thiébaud D, Krieg MA, Gillard-Berguer D, et al. Cyclosporine induces high bone turnover and may contribute to bone loss after heart transplantation. Eur J Clin Invest 1996; 26:549.
  61. Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 1999; 397:530.
  62. Landewe RB, Goei The HS, van Rijthoven AW, et al. Cyclosporine in common clinical practice: an estimation of the benefit/risk ratio in patients with rheumatoid arthritis. J Rheumatol 1994; 21:1631.
  63. Dongari A, McDonnell HT, Langlais RP. Drug-induced gingival overgrowth. Oral Surg Oral Med Oral Pathol 1993; 76:543.
  64. Cutolo M, Giusti M, Villaggio B, et al. Testosterone metabolism and cyclosporin A treatment in rheumatoid arthritis. Br J Rheumatol 1997; 36:433.
  65. Thomas DW, Newcombe RG, Osborne GR. Risk factors in the development of cyclosporine-induced gingival overgrowth. Transplantation 2000; 69:522.
  66. Wong W, Hodge MG, Lewis A, et al. Resolution of cyclosporin-induced gingival hypertrophy with metronidazole. Lancet 1994; 343:986.
  67. Cecchin E, Zanello F, De Marchi S. Treatment of cyclosporine-induced gingival hypertrophy. Ann Intern Med 1997; 126:409.
  68. Gómez E, Sánchez-Nuñez M, Sánchez JE, et al. Treatment of cyclosporin-induced gingival hyperplasia with azithromycin. Nephrol Dial Transplant 1997; 12:2694.
  69. Thorp M, DeMattos A, Bennett W, et al. The effect of conversion from cyclosporine to tacrolimus on gingival hyperplasia, hirsutism and cholesterol. Transplantation 2000; 69:1218.
  70. Talbot D, Rix D, Abusin K, et al. Alopecia as a consequence of tacrolimus therapy in renal transplantation? Transplantation 1997; 64:1631.
  71. Shapiro R, Jordan ML, Scantlebury VP, et al. Alopecia as a consequence of tacrolimus therapy. Transplantation 1998; 65:1284.
  72. Tricot L, Lebbé C, Pillebout E, et al. Tacrolimus-induced alopecia in female kidney-pancreas transplant recipients. Transplantation 2005; 80:1546.