Sirolimus (SRI, Rapamune®, Wyeth-Ayerst, Radnor, PA) is a hydrophobic 31-membered macrocyclic lactone (Figure 1) derived from Streptomyces hygroscopicus, an actinomycete isolated from soil samples taken from the Vai Atari region of Rapa Nui (Easter Island). Macrocyclic lactones are lipophilic molecules bearing a large 12-, 14-, or 16-membered lactone ring substituted with hydroxyl, methyl, and ethyl groups, as well as carbonyl functions with one, two, or three carbohydrate fragments.


Acute Rejection Renal Transplant Recipient Renal Allograft Chronic Rejection Acute Rejection Episode 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kuo CJ, Chung J, Fiorentino DF, et al. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature 1992; 358: 70–73.PubMedCrossRefGoogle Scholar
  2. 2.
    June CH, Ledbetter JA, Gilespie MM, et al. T cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol Cell Biol 1987; 7: 4472–4481.PubMedGoogle Scholar
  3. 3.
    Graves LM, Bornfeldt KE, Argast GM, et al. cAMP-and rapamycin-sensitive regulation of the association of eukaryotic initiation factor 4E and the translational regulator PHAS-I in aortic smooth muscle cells. Proc Natl Acad Sci U S A 1995; 92: 7222–7226.PubMedCrossRefGoogle Scholar
  4. 4.
    Brown EJ, Albers MW, Shin TB, et al. A mammalian protein targeted by Gl-arresting-rapamycin-receptor complex. Nature 1994; 369: 756–758.PubMedCrossRefGoogle Scholar
  5. 5.
    Brown EJ, Beal PA, Keith CT, et al. Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature 1995; 377: 441–446.PubMedCrossRefGoogle Scholar
  6. 6.
    Simm A, Nestler M, Hoppe V. PDGF-AA, a potent mitogen for cardiac fibroblasts from adult rats. J Mol Cell Cardiol 1997; 29: 357–368.PubMedCrossRefGoogle Scholar
  7. 7.
    Akselband Y, Harding MW, Nelson PA. Rapamycin inhibits spontaneous and fibroblast growth factor beta-stimulated proliferation of endothelial cells and fibroblasts. Transplant Proc 1991; 23: 2833–2836.PubMedGoogle Scholar
  8. 8.
    Marx SO, Jayaraman T, Go LO, et al. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res 1995; 76: 412–417.PubMedCrossRefGoogle Scholar
  9. 9.
    Scott PH, Belham CM, al-Hafidh J, et al. A regulatory role for cAMP in phosphatidylinositol 3-kinase/p70 ribosomal S6 kinase-mediated DNA synthesis in platelet-derived-growth-factor-stimulated bovine airway smooth-muscle cells. Biochem J 1996; 318(Pt 3): 965–971.PubMedGoogle Scholar
  10. 10.
    Obata T, Kashiwagi A, Maegawa H, et al. Insulin signaling and its regulation of system A amino acid uptake in cultured rat vascular smooth muscle cells. Circ Res 1996; 79: 1167–1176.PubMedCrossRefGoogle Scholar
  11. 11.
    Kahan BD. Rapamycin: personal algorithms for use based on 250 treated renal allograft recipients. Transplant Proc 1998; 30: 2185–2188.PubMedCrossRefGoogle Scholar
  12. 12.
    Calne RY, Collier DS, Lim S, et al. Rapamycin for immunosuppression in organ allografting. Lancet 1989; 2: 227.PubMedCrossRefGoogle Scholar
  13. 13.
    Stepkowski SM, Chen H, Daloze P, et al. Prolongation by rapamycin of heart, kidney, pancreas, and small bowel allograft survival in rats. Transplant Proc 1991; 23: 507–508.PubMedGoogle Scholar
  14. 14.
    Knight R, Ferraresso M, Serino F, et al. Brief communication: Low-dose rapamycin potentiates the effects of subtherapeutic doses of cyclosporine to prolong renal allograft survival in the mongrel canine model. Transplantation 1993; 55: 947–949.PubMedCrossRefGoogle Scholar
  15. 15.
    Kahan BD, Gibbons S, Tejpal N, et al. Synergistic interactions of cyclosporine and rapamycin to inhibit immune performances of normal human peripheral blood lymphocytes in vitro. Transplantation 1991; 51: 232–239.PubMedCrossRefGoogle Scholar
  16. 16.
    Stepkowski SM, Napoli KL, Wang ME, et al. Effects of the pharmacokinetic interaction between orally administered sirolimus and cyclosporine on the synergistic prolongation of heart allograft survival in rats. Transplantation 1996; 62: 986–994.PubMedCrossRefGoogle Scholar
  17. 17.
    Lown KS, Mayo RR, Leichtman AB, et al. Role of intestinal P-glycoprotein (mdrl) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther 1997; 62: 248–260.PubMedCrossRefGoogle Scholar
  18. 18.
    Hebert MF, Roberts JP, Prueksaritanont T, et al. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther 1992; 52: 453–457.PubMedCrossRefGoogle Scholar
  19. 19.
    Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995; 13: 129–134.PubMedCrossRefGoogle Scholar
  20. 20.
    Kaplan B, Meier-Kriesche HU, Napoli KL, et al. The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent. Clin Pharmacol Ther 1998; 63: 48–53.PubMedCrossRefGoogle Scholar
  21. 21.
    Yatscoff RW, Wang P, Chan K, et al. Rapamycin: distribution, pharmacokinetics, and therapeutic range investigations. Ther Drug Monit 1995; 17: 666–671.PubMedCrossRefGoogle Scholar
  22. 22.
    Zimmerman JJ, Kahan BD. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol 1997; 37: 405–415.PubMedGoogle Scholar
  23. 23.
    Kahan BD, Grevel J. Overview: Optimization of cyclosporine therapy in renal transplantation by a pharmacokinetic strategy. Transplantation 1988; 46: 631–644.PubMedCrossRefGoogle Scholar
  24. 24.
    Napoli KL, Kahan BD. Routine clinical monitoring of sirolimus (rapamycin) whole-blood concentrations by HPLC with ultraviolet detection. Clin Chem 1996; 42: 1943–1948.PubMedGoogle Scholar
  25. 25.
    Kahan BD, Podbielski J, Napoli KL, et al. Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. Transplantation 1998; 66: 1040–1046.PubMedCrossRefGoogle Scholar
  26. 26.
    Lindholm A, Kahan BD. Influence of cyclosporine pharmacokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation. Clin Pharmacol Ther 1993; 54: 205–218.PubMedCrossRefGoogle Scholar
  27. 27.
    Kelly PA, Napoli KL, Dunne C, et al. Conversion from liquid to solid sirolimus formulations in stable renal allograft transplant recipients. Biopharm Drug Dispos (in press).Google Scholar
  28. 28.
    Kahan BD, for the Rapamune U.S. Study Group. A phase III comparative efficacy trial of Rapamune in renal allograft recipients [Abstract 198]. XVII World Congress, Montreal, Canada, 1998.Google Scholar
  29. 29.
    Murgia MG, Jordan S, Kahan BD. The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Kidney Int 1996; 49: 209–216.PubMedCrossRefGoogle Scholar
  30. 30.
    Kahan BD, Julian BA, Pescovitz MD, et al. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in Caucasian recipients of mismatched primary renal allografts: a phase II trial. Transplantation (in press).Google Scholar
  31. 31.
    Groth CG, Backman L, Morales JM, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999; 67: 1036–1042.PubMedCrossRefGoogle Scholar
  32. 32.
    MacDonald AS for the Rapamune Global Study Group. A randomized, placebo-controlled trial of Rapamune in primary renal allograft recipients [Abstract 426]. Abstracts of the Transplantation Society XXVII World Congress, Montreal, 1998.Google Scholar
  33. 33.
    DiJoseph JF, Sharma RN, Chang JY. The effect of rapamycin on kidney function in the Sprague-Dawley rat. Transplantation 1992; 53: 507–513.PubMedCrossRefGoogle Scholar
  34. 34.
    Hong JC, Kahan BD. Use of anti-CD25 monoclonal antibody in combination with rapamycin to eliminate cyclosporine treatment during the induction phase of immunosuppression [Brief Communication]. Transplantation 1999; 68: 701–704.PubMedCrossRefGoogle Scholar
  35. 35.
    Vincenti F, Kirkman R, Light S, et al. Interleukin-2 receptor blockade with daclizumab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group. N Engl J Med 1998; 338: 161–165.PubMedCrossRefGoogle Scholar
  36. 36.
    Kahan, B.D., Rajagopalan, P.R., and Hall, M., for the United States Simulect8 Renal Study Group. Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2-receptor monoclonal antibody. Transplantation 1999; 67: 276–284.PubMedCrossRefGoogle Scholar
  37. 37.
    Pescovitz MD, Kahan BD, Julian B, et al. Sirolimus (SRL) permits early steroid withdrawal from a triple therapy renal prophylaxis regimen. XVI Annual Meeting of the American Society for Transplant Physicians, 1997.Google Scholar
  38. 38.
    Slaton JW, Kahan BD. Case report—sirolimus rescue therapy for refractory renal allograft rejection. Transplantation 1996; 61: 977–979.PubMedCrossRefGoogle Scholar
  39. 39.
    Kahan BD, Podbielski J, Van Buren CT. Rapamycin for refractory renal allograft rejection [Abstract #711]. XVII Annual Meeting of the American Society of Transplant Physicians, 1998.Google Scholar
  40. 40.
    Kahan BD. The role of rapamycin in chronic rejection prophylaxis: a theoretical consideration. Graft 1998; 1 (2 Suppl II): 93–96.Google Scholar
  41. 41.
    Gregory CR, Huang X, Pratt RE, et al. Treatment with rapamycin and mycophenolic acid reduces arterial intimal thickening produced by mechanical injury and allows endothelial replacement. Transplantation 1995; 59: 655–661.PubMedCrossRefGoogle Scholar
  42. 42.
    Gallo R, Padurean A, Jayaraman T, et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation 1999; 99: 2164–2170.PubMedCrossRefGoogle Scholar
  43. 43.
    Morris RE, Huang X, Gregory CR, et al. Studies in experimental models of chronic rejection: use of rapamycin (sirolimus) and isoxazole derivatives (leflunomide and its analogue) for the suppression of graft vascular disease and obliterative bronchiolitis. Transplant Proc 1995; 27: 2068–2069.PubMedGoogle Scholar
  44. 44.
    Meiser BM, Billingham ME, Morris RE. Effects of cyclosporin, FK506, and rapamycin on graft-vessel disease. Lancet 1991; 338: 1297.PubMedCrossRefGoogle Scholar
  45. 45.
    Schmid C, Heemann U, Tilney NL. Factors contributing to the development of chronic rejection in heterotopic rat heart transplantation. Transplantation 1997; 64: 222–228.PubMedCrossRefGoogle Scholar
  46. 46.
    Kahan BD, Mickey R, Flechner SM, et al. Multivariate analysis of risk factors impacting on immediate and eventual cadaver allograft survival in cyclosporine-treated recipients. Transplantation 1987; 43(1): 65–70.PubMedCrossRefGoogle Scholar
  47. 47.
    Almond PS, Matas A, Gillingham K, et al. Risk factors for chronic rejection in renal allograft recipients. Transplantation 1993; 55: 752–756.PubMedCrossRefGoogle Scholar
  48. 48.
    Napoli KL, Wang ME, Stepkowski SM, et al. Relative tissue distributions of cyclosporine and sirolimus after concomitant peroral administration to the rat: evidence for pharmacokinetic interactions. Ther Drug Monit 1998; 20: 123–133.PubMedCrossRefGoogle Scholar
  49. 49.
    Podder H, Stepkowski SM, Napoli KL, et al. Sirolimus exacerbates CsA-induced nephrotoxicity by raising CsA blood trough levels, but does not impair renal function by a pharmacodynamic interaction [Abstract #206]. XVIII Annual Scientific Meeting of the American Society of Transplant Physicians, 1999.Google Scholar
  50. 50.
    Dimeny E, Fellstrom B, Larsson E, et al. Hyperlipoproteinemia in renal transplant recipients: is there a linkage with chronic vascular rejection? Transplant Proc 1993; 25: 2065–2066.PubMedGoogle Scholar
  51. 51.
    Dimeny E, Tufveson G, Lithell H, et al. The influence of pretransplant lipoprotein abnormalities on the early results of renal transplantation. Eur J Clin Invest 1993; 23: 572–579.PubMedCrossRefGoogle Scholar
  52. 52.
    Eichenwald HF. Adverse reactions to erythromycin. Pediatr Infect Dis 1986; 5: 147–150.PubMedCrossRefGoogle Scholar
  53. 53.
    Hodak SP, Moubarak JB, Rodriquez I, et al. QT prolongation and near fatal cardiac arrhythmia after intravenous tacrolimus administration: a case report. Transplantation 1998; 66: 535–537.PubMedCrossRefGoogle Scholar
  54. 54.
    Johnson MC, So S, Marsh JW, et al. QT prolongation and Torsades de Pointes after administration of FK506. Transplantation 1992; 53: 929–930.PubMedCrossRefGoogle Scholar
  55. 55.
    Antzelevitch C, Sun ZQ, Zhang ZQ, et al. Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes. J Am Coll Cardiol 1996; 28: 1836–1848.PubMedCrossRefGoogle Scholar
  56. 56.
    Drici MD, Knollmann BC, Wang WX, et al. Cardiac actions of erythromycin: influence of female sex. JAMA 1998; 280: 1774–1776.PubMedCrossRefGoogle Scholar
  57. 57.
    Guelon D, Bedock B, Chartier C, et al. QT prolongation and recurrent “torsades de pointes” during erythromycin lactobionate infusion. Am J Cardio 1986; 58: 666.CrossRefGoogle Scholar
  58. 58.
    Kahan BD, Wong RL, Carter C, et al. A phase I study of a four-week course of the rapamycin analogue SDZ-RAD (RAD) in quiescent cyclosporine-prednisone-treated renal transplant recipients. Transplantation (in press).Google Scholar
  59. 59.
    Hong JC, Kahan BD. Two paradigms for new immunosuppressive strategies in organ transplantation. Curr Opin Organ Transplant 1998; 3: 175–182.Google Scholar
  60. 60.
    Mahalati K, McAlister V, Peltikian K, et al. A clinical pharmacokinetic study of tacrolimus and sirolimus combination immunosuppression [Abstract #105]. 18th Annual Scientific Meeting of the American Society of Transplantation, 1999.Google Scholar
  61. 61.
    Dumont FJ, Melino MR, Staruch MJ, et al. The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells. J Immunol 1990; 144: 1418–1424.PubMedGoogle Scholar
  62. 62.
    Chen H, Qi S, Xu D, et al. Combined effect of rapamycin and FK 506 in prolongation of small bowel graft survival in the mouse. Transplant Proc 1998; 30: 2579–2581.PubMedCrossRefGoogle Scholar
  63. 63.
    Vu MD, Qi S, Xu D, et al. Tacrolimus (FK506) and sirolimus (rapamycin) in combination are not antagonistic but produce extended graft survival in cardiac transplantation in the rat. Transplantation 1997; 64: 1853–1856.PubMedCrossRefGoogle Scholar
  64. 64.
    Vu MD, Qi S, Xu D, et al. Synergistic effects of mycophenolate mofetil and sirolimus in prevention of acute heart, pancreas, and kidney allograft rejection and in reversal of ongoing heart allograft rejection in the rat. Transplantation 1998; 66: 1575–1580.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Barry D. Kahan

There are no affiliations available

Personalised recommendations