Skip to main content
Log in

Clinically Significant Drug Interactions with New Immunosuppressive Agents

  • Review Article
  • Drug Experience
  • Published:
Drug Safety Aims and scope Submit manuscript

Summary

Tacrolimus (FK506), mycophenolate mofetil, sirolimus (rapamycin), gusperimus, and monoclonal antibody preparations are new immunosuppressive agents, some of which are already approved for clinical use, while others are currently undergoing clinical trials. The present article provides an overview of adverse drug interactions between these immunosuppressants and other drugs which may be used concomitantly.

Preliminary data suggest that a pharmacodynamic interaction can occur between tacrolimus and nonsteroidal anti-inflammatory drugs, associated with an increased risk of nephrotoxicity. Erythromycin, clarithromycin, clotrimazole, fluconazole, ketoconazole, and danazol have been shown to increase tacrolimus blood concentrations, while rifampicin (rifampicin) was found to decrease tacrolimus blood concentrations. Evidence from experimental studies suggest that several other drugs also known to affect cytochrome P450 activity may have significant effects on the pharmacokinetics of tacrolimus. On the other hand, tacrolimus itself may inhibit the metabolism of coadministered drugs. This interaction may be attributed to the enhanced renal impairment which has been observed in patients treated with tacrolimus and cyclosporin.

The bioavailability of mycophenolic acid, the active metabolite of mycophenolate mofetil, has been reported to be reduced by aluminium/magnesium hydroxide-containing antacids and cholestyramine. Mycophenolic acid, sirolimus and gusperimus may impair bone marrow function and this adverse effect may be enhanced by concomitant administration of other myelosuppressive drugs.

There is some evidence that coadministered sirolimus and cyclosporin cause an increase in each other’s blood concentrations. An increased risk of central nervous system adverse effects has been described following the combined use of indomethacin and the monoclonal antibody muromonab CD3 (OKT3).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Campana C, Regazzi MB, Buggia I, et al. Clinically significant drug interactions with cyclosporin. Clin Pharmacokinet 1996; 30: 141–79

    Article  PubMed  CAS  Google Scholar 

  2. Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit 1995; 17: 584–91

    Article  PubMed  CAS  Google Scholar 

  3. Peters DH, Fitton A, Plosker GL, et al. Tacrolimus: a review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 1993; 46: 746–94

    Article  PubMed  CAS  Google Scholar 

  4. Sheiner PA, Mor E, Chodoff L, et al. Acute renal failure associated with the use of ibuprofen in two liver transplant recipients on FK506. Transplantation 1993; 57: 1132–3

    Google Scholar 

  5. Jensen C, Jordan M, Shapiro R, et al. Interaction between tacrolimus and erythromycin [letter]. Lancet 1994; 344: 825

    Article  PubMed  CAS  Google Scholar 

  6. Wolter K, Wagner K, Philipp T, et al. Interaction between FK506 and clarithromycin in a renal transplant patient. Eur J Clin Pharmacol 1994; 47: 207–8

    PubMed  CAS  Google Scholar 

  7. Mieles L, Venkataramanan R, Yokoyama I, et al. Interaction between FK506 and clotrimazole in a liver transplant recipient. Transplantation 1991; 52: 1086–7

    Article  PubMed  CAS  Google Scholar 

  8. Manez R, Martin M, Venkataramanan R, et al. Fluconazole therapy in transplant recipients receiving FK506. Transplantation 1994; 57: 1521–35

    PubMed  CAS  Google Scholar 

  9. Assan R, Fredj G, Larger E, et al. FK 506/Fluconazole interaction enhances FK 506 nephrotoxicity. Diabete Metab 1994; 20: 49–52

    PubMed  CAS  Google Scholar 

  10. Shapior R, Venkataramanan R, Warty VS, et al. FK506 interaction with danazol. Lancet 1993; I: 1344–5

    Article  Google Scholar 

  11. Furlan V, Perello L, Jacquemin E, et al. Interactions between FK506 and rifampicin or erythromycin in pediatric liver recipients. Transplantation 1995; 59: 1217–8

    PubMed  CAS  Google Scholar 

  12. Rui X, Flowers J, Warty V, et al. Drug interactions with FK 506 [abstract]. Pharm Res 1992; 9: S291

    Article  Google Scholar 

  13. Christians U, Schmidt G, Bader A, et al. Identification of drug inhibiting the in vitro metabolism of tacrolimus by human liver microsomes. Br J Clin Pharmacol 1996; 41: 187–90

    Article  PubMed  CAS  Google Scholar 

  14. Iwasaki K, Matsuda H, Nagase K, et al. Effects of twenty-three drugs on the metabolism of FK506 by human liver microsomes. Res Commun Chem Pathol Pharmacol 1993; 82: 209–16

    PubMed  CAS  Google Scholar 

  15. Steeves M, Abdallah R, Venkataramanan R, et al. ln-vitro interaction of a novel immunosuppressant FK506, and antacids. J Pharm Pharmacol 1991; 43: 574–7

    Article  PubMed  CAS  Google Scholar 

  16. Venkataramanan R, Swaminathan A, Prasad T, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet 1995; 29: 404–30

    Article  PubMed  CAS  Google Scholar 

  17. Matsuda H, Iwasaki K, Shiraga T, et al. Interactions of FK506 (tacrolimus) with clinically important drugs. Res Commun Mol Pathol Pharmacol 1996; 91: 57–64

    PubMed  CAS  Google Scholar 

  18. Shaeffer MS, Collier D, Sorrell MF. Interaction between FK506 and erythromycin [letter]. Ann Pharmacother 1994; 28: 280–1

    PubMed  CAS  Google Scholar 

  19. Zeevi A, Burckart G, Jain A, et al. Bioassay of plasma specimens from liver transplant patients on FK506 immunosuppression. Transplant Proc 1990; 22: 60–3

    PubMed  CAS  Google Scholar 

  20. Krentz AJ, Dmitrewski J, Mayer D, et al. Effects of immunosuppressive agents on glucose metabolism: implications for the development of post-transplant diabetes mellitus. Clin Immunother 1995; 4: 103–23

    Article  Google Scholar 

  21. Rossi SJ, Schroeder TJ, Hariharan S. Prevention and management of the adverse effects associated with immunosuppressive therapy. Drug Saf 1993; 9: 104–31

    Article  PubMed  CAS  Google Scholar 

  22. Bailey DG, Arnold JM, Spence JD. Grapefruit juice and drugs: how significant is this interaction? Clin Pharmacokinet 1994; 26: 91–8

    Article  PubMed  CAS  Google Scholar 

  23. Christians U, Braun F, Sattler M, et al. Interactions of FK506 and cyclosporine metabolism. Transplant Proc 1991; 23: 2794–6

    PubMed  CAS  Google Scholar 

  24. Omar G, Shah IA, Thomson AW, et al. FK506 inhibition of cyclosporine metabolism by human liver microsomes. Transplant Proc 1991; 23: 934–5

    PubMed  CAS  Google Scholar 

  25. Starzl TE, Todo S, Fung J, et al. FK506 for liver, kidney, and pancreas transplantation. Lancet 1989; II: 1000–4

    Article  Google Scholar 

  26. Jain AB, Venkataramanan R, Fung J, et al. Pharmacokinetics of cyclosporine and nephrotoxicity in orthotopic liver transplant patients rescued with FK506. Transplant Proc 1991; 23: 2777–9

    PubMed  CAS  Google Scholar 

  27. McCauley J, Takaya S, Fung J, et al. The question of FK506 nephrotoxicity after liver transplantation. Transplant Proc 1991; 23: 1444–7

    PubMed  CAS  Google Scholar 

  28. Goss JE, Ramo BW, Blake K. Torsades de pointes associated with astemizole (Hismanal) therapy [letter]. Arch Intern Med 1993; 153: 2705

    Article  PubMed  CAS  Google Scholar 

  29. Pohjola-Sintonen S, Viitasalo M, Toivonen L, et al. Itraconazole prevents terfenadine metabolism and increases risk of torsades de pointes ventricular tachycardia. Eur J Clin Pharmacol 1993; 45: 191–3

    Article  PubMed  CAS  Google Scholar 

  30. Morris RE. Mechanisms of action of new immunosuppressive drugs. Kidney Int 1996; 49: 26–38

    Article  Google Scholar 

  31. Fulton B, Markham A. Mycophenolate mofetil: a review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation. Drugs 1996; 51: 278–98

    Article  PubMed  CAS  Google Scholar 

  32. Sollinger HW for the U.S. Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995; 60: 225–32

    Article  PubMed  CAS  Google Scholar 

  33. European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet 1995; I: 1321–5

    Google Scholar 

  34. Hoffmann-La Roche Inc. Mycophenolate mofetil prescribing information. 1995

  35. Shah J, Juan D, Bullingham R, et al. A single dose drug interaction study of mycophenolate mofetil and acyclovir in normal subjects [abstract]. J Clin Pharmacol 1994; 34: 1029

    Google Scholar 

  36. Bullingham R, Monroe S, Nicholls A, et al. Pharmacokinetics and bioavailability of mycophenolate mofetil in healthy subjects after single-dose oral and intravenous administration. J Clin Pharmacol 1996; 36: 315–24

    PubMed  CAS  Google Scholar 

  37. Parker G, Bullingham R, Kamm B, et al Pharmacokinetics of oral mycophenolate mofetil in volunteer subjects with varying degrees of hepatic oxidative impairment. J Clin Pharmacol 1996; 36: 332–44

    PubMed  CAS  Google Scholar 

  38. Wolfe EJ, Mathur VS, Tomlanovich S, et al. Pharmacokinetic drug interaction study of mycophenolate mofetil and IV ganciclovir in renal transplant patients [abstract]. Clin Pharmacol Ther 1995; 57: 148

    Google Scholar 

  39. Allison AC, Eugui EM. The design and development of an immunosuppressive drug, mycophenolate mofetil. Springer Semin Immunopathol 1993; 14: 353–80

    Article  PubMed  CAS  Google Scholar 

  40. Allison AC, Eugui EM. Mycophenolate mofetil (RS-61443): mode of action and effects on graft rejection. In: Thomson AW, Starzl TE, editors. Immunosuppressive drugs: developments in antirejection therapy. London: Edward Arnold, 1994: 141–59

    Google Scholar 

  41. Morris RE. Rapamycins: antifungal, antitumor, antiproliferative, and immunosuppressive macrolides. Transplant Rev 1992; 6: 39–87

    Article  Google Scholar 

  42. Sehgal SN. Rapamune (sirolimus, rapamycin): an overview and mechanism of action. Ther Drug Monit 1995; 17: 660–5

    Article  PubMed  CAS  Google Scholar 

  43. Murgia MG, Jordan S, Kahan BD. The side effect of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Kidney Int 1996; 49: 209–16

    Article  PubMed  CAS  Google Scholar 

  44. Whiting PH, Woo J, Adam BJ, et al. Toxicity of rapamycin — a comparative and combination study with cyclosporine at immunotherapeutic dosage in the rat. Transplantation 1991; 52: 203–8

    Article  PubMed  CAS  Google Scholar 

  45. Andoh TF, Burdmann EA, Fransechini N, et al. Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. Kidney Int 1996; 50: 1110–7

    Article  PubMed  CAS  Google Scholar 

  46. Stepkowski SM, Napoli KL, Wang M-E, 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: 986–94

    Article  PubMed  CAS  Google Scholar 

  47. Meier-Knesche H-U, Napoli KL, Jordan S, et al. Concentration-dependent pharmacokinetic interaction between oral cyclosporine and sirolimus in renal transplant recipients [abstract]. American Society of Transplant Physicians 15th Annual Meeting: 1996 May 26–30; Texas, 323

  48. Nadler SG, Eversole ACB, Tepper MA, et al. Elucidating the mechanism of action of the immunosuppressant 15-deoxyspergualin. Ther Drug Monit 1995; 17: 700–3

    Article  PubMed  CAS  Google Scholar 

  49. Suzuki S. Deoxyspergualin: mode of action and effects on graft rejection. In: Thomson AW, Starzl TE, editors. Immunosuppressive drugs: developments in antirejection therapy. London: Edward Arnold, 1994: 187–202

    Google Scholar 

  50. Ohlman S, Gannedahl G, Tyden G, et al. Treatment of renal transplant rejection with 15-deoxyspergualin — a dose-finding study in man. Transplant Proc 1992; 24: 318–20

    PubMed  CAS  Google Scholar 

  51. Amemiya H, Ota K, Sonoda T, et al. Pulse therapy for rejection with deoxyspergualin in renal recipients: a multicenter controlled study. Transplant Proc 1992; 24: 1375–6

    PubMed  CAS  Google Scholar 

  52. Todd PA, Brogden RN. Muromonab CD3: a review of its pharmacology and therapeutic potential. Drugs 1989; 37: 871–99

    Article  PubMed  CAS  Google Scholar 

  53. Thistlethwaite JR, Gaber AO, Haag BW, et al. OKT3 treatment of steroid-resistant renal allograft rejection. Transplantation 1987; 43: 176–84

    Article  PubMed  Google Scholar 

  54. Ortho Multicenter Transplant Study Group. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 1985; 313: 337–42

    Article  Google Scholar 

  55. Van Aken WG, Eikhout HW. Blood, blood components, plasma and plasma products. In: Aronson JK, Van Boxtel CJ, editors. Side effects of drug annual 18. Amsterdam: Elsevier, 1995: 342–57

    Google Scholar 

  56. Li PKT, Nicholls MG, Lai KN. The complications of newer transplant antirejection drugs: treatment with cyclosporin A, OKT3, and FK 506. Adverse Drug React Acute Poisoning Rev 1990; 9: 123–55

    PubMed  CAS  Google Scholar 

  57. Coleman AE, Norman DJ. OKT3 encephalopathy. Ann Neurol 1990; 28: 837–8

    Article  PubMed  CAS  Google Scholar 

  58. Abramowicz D, Schandene L, Goldman M, et al. Release of tumor necrosis factor-alpha, interleukin-2 and interferongamma in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients. Transplantation 1989; 47: 606–8

    Article  PubMed  CAS  Google Scholar 

  59. Chan GL, Weinstein SS, Wright CE, et al. Encephalopathy associated with OKT3 administration: possible interactions with Indomethacin. Transplantation 1991; 52: 148–50

    Article  PubMed  CAS  Google Scholar 

  60. Gotz V. Paranoid psychosis with indomethacin [letter]. BMJ 1978; 1: 49

    Article  PubMed  CAS  Google Scholar 

  61. Carney MW. Paranoid psychosis with indomethacin. BMJ 1977; 2: 994–5

    Article  PubMed  CAS  Google Scholar 

  62. Rothermich NO. An extended study of indomethacin. JAMA 1966; 195: 531–6

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mignat, C. Clinically Significant Drug Interactions with New Immunosuppressive Agents. Drug-Safety 16, 267–278 (1997). https://doi.org/10.2165/00002018-199716040-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-199716040-00004

Keywords

Navigation