Corticosteroid Interactions with Cyclosporine,Tacrolimus,Mycophenolate,and Sirolimus: Fact or Fiction?

Halloran PR Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004; 351: 2715–29. DOI 10.1056/NEJMra033540

Product monograph. Cellcept (mycophenolate mofetil). Nutley, NJ: Roche Laboratories, March 2003.

Kahan BD , Napoli KL . Sirolimus. In: Burton ME , Shaw LM , Schentag JJ , Evans WE , eds. Applied pharmacokinetics & pharmacodynamics. Principles of therapeutic drug monitoring. 4th ed. Baltimore: Lippincott Williams & Wilkins, 2006: 595–616.

Hiatt WR , Nissen SE , Cardiovascular and Renal Drugs Advisory Committee, US Food and Drug Administration. New drug application 21–628, certican (everolimus), for the proposed indication of prophylaxis of rejection in heart transplantation: report from the Cardiovascular and Renal Drugs Advisory Committee, US Food and Drug Administration, November 16, 2005, Rockville, MD. Circulation 2006;113:e394–5. DOI 10.1161/CIRCULATIONAHA.105.607630

Novartis Pharmaceutical Corporation. New Novartis drug Certican approved in first European market, www.novartis.nl/pdf/nieuws/juli2003/pr230703certicanapprovalsweden.pdf (accessed 2008 Feb 18).

Karin M. New twists in gene regulation by glucocorticoid receptor: is DNA binding dispensable? Cell 1998;93:487–90. DOI S0092-8674(00)81177-0

Smith L. Corticosteroids in solid organ transplantation: update and review of the literature. J Pharm Pract 2003;16:380–7.

Johnston A , Holt DW . Cyclosporine. In: Burton ME , Shaw LM , Schentag JJ , Evans WE , eds. Applied pharmacokinetics & pharmacodynamics. Principles of therapeutic drug monitoring. 4th ed. Baltimore: Lippincott Williams & Wilkins, 2006: 512–28.

Chapman TM , Perry CM . Everolimus. Drugs 2004;64:861–72; discussion 873–4.

Product monograph. Prograf (tacrolimus). Markham, ON: Fujisawa Canada Inc., February 2004.

Sattler M , Guengerich FP , Yun CH , Christians U , Sewing KF . Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat. Drug Metab Dispos 1992;20:753–61.

Shiraga T , Matsuda H , Nagase K. Metabolism of FK506, a potent immunosuppressive agent, by cytochrome P450 3A enzymes in rat, dog and human liver microsomes. Biochem Pharmacol 1994;47:727–35. DOI 0006-2952(94)90136-8

Augustine JJ , Hricik DE . Steroid sparing in kidney transplantation: changing paradigms, improving outcomes, and remaining questions. Clin J Am Soc Nephrol 2006;1:1080–9. DOI 10.2215/CJN.01800506

Bestard O , Cruzado JM , Grinyo JM . Corticosteroid-sparing strategies in renal transplantation: are we still balancing rejection risk with improved tolerability? Drugs 2006;66:403–14.

Fireman M , DiMartini AF , Armstrong SC , Cozza KL . Immunosuppressants. Psychosomatics 2004;45:354–60.

Hollander AA , Hene RJ , Hermans J , van Es LA , van der Woude FJ . Late prednisone withdrawal in cyclosporine-treated kidney transplant patients: a randomized study. J Am Soc Nephrol 1997;8:294–301.

Lemieux I , Houde I , Pascot A. Effects of prednisone withdrawal on the new metabolic triad in cyclosporine-treated kidney transplant patients. Kidney Int 2002;62:1839–47. DOI 10.1046/j.1523-1755.2002.00611.x

Rigotti P , European Tacrolimus/MMF Transplantation Study Group. Patiente with high cholesterol levels benefit most from early withdrawal of corticosteroids. Transplant Proc 2002;34:1797–8. DOI S0041134502030828

Ramirez CB , Sebayel MI , Kizilisik T. Early steroid withdrawal after liver transplantation. Transplant Proc 1998;30:3182–3.

Rosenbaum DH , Adams BC , Mitchell JD . Effects of early steroid withdrawal after heart transplantation. Ann Thorac Surg 2006;82:637–44; discussion 644. DOI 10.1016/j.athoracsur.2006.03.067

Vazquez de Prada JA , Celemin I , de la Torre JM . Corticosteroid withdrawal after heart transplantation. Transplant Proc 1999;31:2212–4.

Pichard L , Fabre I , Daujat M , Domergue J , Joyeux H , Maurel P. Effect of corticosteroids on the expression of cytochromes P450 and on cyclosporin A oxidase activity in primary cultures of human hepatocytes. Mol Pharmacol 1992;41:1047–55.

Christians U , Pokaiyavanichkul T , Chan L. Tacrolimus. In: Burton ME , Shaw LM , Schentag JJ , Evans WE , eds. Applied pharmacokinetics & pharmacodynamics. Principles of therapeutic drug monitoring. 4th ed. Baltimore: Lippincott Williams & Wilkins, 2006: 529–62.

Pichard L , Fabre I , Fabre G. Cyclosporin A drug interactions. Screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes. Drug Metab Dispos 1990;18:595–606.

Yates CR , Chang C , Kearbey JD . Structural determinants of P-gly-coprotein–mediated transport of glucocorticoids. Pharm Res 2003;20:1794–803.

Lemahieu WP , Maes BD , Verbeke K , Vanrenterghem YF . Alterations of CYP3A4 and P-glycoprotein activity in vivo with time in renal graft recipients. Kidney Int 2004;66:433–40. DOI 10.HH/j.1523-1755.2004.00750jc

Konishi H , Sumi M , Shibata N , Takada K , Minouchi T , Yamaji A. Decrease in oral bioavailability of Ciclosporin by intravenous pulse of methylprednisolone succinate in rats. J Pharm Pharmacol 2004;56:1259–66. DOI 10.1211/0022357044481

Joy MS , Nickeleit V , Hogan SL , Thompson BD , Finn WF . Calcineurin inhibitor-induced nephrotoxicity and renal expression of P-glycoprotein. Pharmacotherapy 2005;25:779–89.

Watkins PB , Murray SA , Winkelman LG , Heuman DM , Wrighton SA , Guzelian PS . Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450. Studies in rats and patients. J Clin Invest 1989;83:688–97.

McCune JS , Hawke RL , LeCluyse EL . In vivo and in vitro induction of human cytochrome P4503A4 by dexamethasone. Clin Pharmacol Ther 2000;68:356–66. DOI10.1067/mcp2000.110215.

Soars MG , Petullo DM , Eckstein JA , Kasper SC , Wrighton SA . An as sessment of UDP-glucuronosyltransferase induction using primary hu man hepatocytes. Drug Metab Dispos 2004;32:140–8. DOI 10.1124/dmd.32.1.140

Kanou M , Usui T , Ueyama H , Sato H , Ohkubo I , Mizutani T. Stimulation of transcriptional expression of human UDP-glucuronosyltransferase 1A1 by dexamethasone. Mol Biol Rep 2004;31:151–8.

Djebli N , Picard N , Rerolle JP , Le Meur Y , Marquet P. Influence of the UGT2B7 promoter region and exon 2 polymorphisms and comedications on acyl-MPAG production in vitro and in adult renal transplant patients. Pharmacogenet Genomics 2007;17:321–30. DOI 10.1097/FPC.0b013e32801430f8

Li YQ , Prentice DA , Howard ML , Mashford ML , Desmond PV . The effect of hormones on the expression of five isoforms of UDP-glucuronosyltransferase in primary cultures of rat hepatocytes. Pharm Res 1999;16:191–7.

Wishart GJ , Dutton GJ . Regulation of onset of development of UDP-glucuronosyltransferase activity towards O-aminophenol by glucocorticoids in late-foetal rat liver in utero. Biochem J 1977;168:507–11.

Ueda K , Saeki T , Hirai M. Human P-glycoprotein as a multi-drug transporter analyzed by using transepithelial transport system. Jpn J Physiol 1994;44(suppl 2):S67–71.

Schuetz EG , Beck WT , Schuetz JD . Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Mol Pharmacol 1996;49:311–8.

Demeule M , Jodoin J , Beaulieu E , Brossard M , Beliveau R. Dexamethasone modulation of multidrug transporters in normal tissues. FEBS Lett 1999;442:208–14. DOI S0014-5793(98)01663-9

Zhao JY , Ikeguchi M , Eckersberg T , Kuo MT . Modulation of multidrug resistance gene expression by dexamethasone in cultured hepatoma cells. Endocrinology 1993;133:521–8.

Salphati L , Benêt LZ . Modulation of P-glycoprotein expression by cytochrome P450 3A inducers in male and female rat livers. Biochem Pharmacol 1998;55:387–95. DOI S0006-2952(97)00436-X

Yokogawa K , Shimada T , Higashi Y. Modulation of mdrla and CYP3A gene expression in the intestine and liver as possible cause of changes in the cyclosporin A disposition kinetics by dexamethasone. Biochem Pharmacol 2002;63:777–83. DOI S00062952010091IX

Pulaski L , Kania K , Ratajewski M , Uchiumi T , Kuwano M , Bartosz G. Differential regulation of the human MRP2 and MRP3 gene expression by glucocorticoids. J Steroid Biochem Mol Biol 2005;96:229–34. DOI 10.1016/j.jsbmb.2005.03.004

Courtois A , Payen L , Guillouzo A , Fardel O. Up-regulation of multidrug resistance–associated protein 2 (MRP2) expression in rat hepatocytes by dexamethasone. FEBS Lett 1999;459:381–5.

Turncliff RZ , Meier PJ , Brouwer KL . Effect of dexamethasone treatment on the expression and function of transport proteins in sandwich-cultured rat hepatocytes. Drug Metab Dispos 2004;32:834–9.

Micuda S , Fuksa L , Brcakova E. Zonation of multidrug resistance–associated protein 2 in rat liver after induction with dexamethasone. J Gastroenterol Hepatol 2007. DOI 10.1111/j.1440-1746.2007.05066.x

Kelly PA , Wang H , Napoli KL , Kanan BD , Strobel HW . Metabolism of cyclosporine by cytochromes P450 3A9 and 3A4. Eur J Drug Metab Pharmacokinet 1999;24:321–8.

Kronbach T , Fischer V , Meyer UA . Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs. Clin Pharmacol Ther 1988;43:630–5. DOI 0009-9236(88)90006-9

Brunner LJ , Bennett WM , Koop DR . Cyclosporine suppresses rat hepatic cytochrome P450 in a time-dependent manner. Kidney Int 1998;54:216–23. DOI 10.1046/j.1523-1755.1998.00970.x

Saeki T , Ueda K , Tanigawara Y , Hori R , Komano T. Human P-glycoprotein transports cyclosporin A and FK506. J Biol Chem 1993;268:6077–80.

Christians U , Jacobsen W , Benet LZ , Lampen A. Mechanisms of clinically relevant drug interactions associated with tacrolimus. Clin Pharmacokinet 2002;41:813–51. DOI 411103

Hesselink DA , van Hest RM , Mathot RA . Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance–associated protein 2. Am J Transplant 2005;5:987–94. DOI 10.1046/j.1600-6143.2005.00779.x

Zucker K , Tsaroucha A , Olson L , Esquenazi V , Tzakis A , Miller J. Evidence that tacrolimus augments the bioavailability of mycophenolate mofetil through the inhibition of mycophenolic acid glucuronidation. Ther Drug Monit 1999;21:35–43.

Staatz CE , Tett SE . Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet 2007;46:13–58.

Zimmerman JJ . Exposure-response relationships and drug interactions of sirolimus. AAPS J 2004;6:e28. DOI 10.1208/aapsj060428

Miller DS , Flicker G , Drewe J. P-glycoprotein-mediated transport of a fluorescent rapamycin derivative in renal proximal tubule. J Pharmacol Exp Ther 1997;282:440–4.

Anglicheau D , Pallet N , Rabant M. Role of P-glycoprotein in cy-closporine cytotoxicity in the cyclosporine-sirolimus interaction. Kidney Int 2006;70:1019–25. DOI 10.1O38/sjJci.5O01649

Wilkinson GR . Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352:2211–21. DOI 10.1056/NEJMra032424

Guengerich FP . Cytochrome P-450 3A4: regulation and role in drug me tabolism. Annu Rev Pharmacol Toxicol 1999;39:1–17. DOI 10.1146/annurev.pharmtox.39.1.1

Guillemette C. Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 2003;3:136–58. DOI 10.1038/sj.tpj.6500171

Kiang TK , Ensom MH , Chang TK . UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther 2005;106:97–132. DOI S0163-7258(04)00200-1 [pii]; 10.1016/j.pharmthera.2004.10.013

Zhang Y , Benet LZ . The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet 2001;40:159–68.

Watkins PB . The barrier function of CYP3A4 and P-glycoprotein in the small bowel. Adv Drug Deliv Rev 1997;27:161–70. DOI S0169-409X(97)00041-0

Benet LZ , Izumi T , Zhang Y , Silverman JA , Wacher VJ . Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery. J Control Release 1999;62:25–31. DOI S0168-3659(99)0O034-6

Suzuki H , Sugiyama Y. Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine. Eur J Pharm Sci 2000;12:3–12. DOI S0928-0987(00)00178-0

Matheny CJ , Lamb MW , Brouwer KR , Pollack GM . Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy 2001;21:778–96.

Lemahieu WP , Maes BD , Vanrenterghem Y. Different evolution of trough and dose levels during the first year after transplantation for tacrolimus versus cyclosporine. Transplant Proc 2005;37:2051–3. DOI 10.1016/j.transproceed2005.03.095

Lemahieu WP , Maes BD , Verbeke K , Vanrenterghem Y. CYP3A4 and P-glycoprotein activity in healthy controls and transplant patients on cyclosporin vs. tacrolimus vs. sirolimus. Am J Transplant 2004;4:1514–22. DOI 10.1111/j.1600-6143.2004.00539.x

Staatz CE , Tett SE . Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet 2004;43:623–53.

Saitoh H , Saikachi Y , Kobayashi M. Limited interaction between tacrolimus and P-glycoprotein in the rat small intestine. Eur J Pharm Sci 2006;28:34–42. DOI 10.1016/j.ejps.2005.12.006

Product monograph. Rapamune (sirolimus). Philadelphia: Wyeth Pharmaceuticals Inc., March 2005.

Arceci RJ , Stieglitz K , Bierer BE . Immunosuppressants FK506 and rapamycin function as reversal agents of the multidrug resistance phenotype. Blood 1992;80:1528–36.

Tsao L , Hsi ED . The clínicopathologic spectrum of posttransplantation lymphoproliferative disorders. Arch Pathol Lab Med 2007;131:1209–18.

Suzuki H , Sugiyama Y. Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2/ABCC2): its impact on drug disposition. Adv Drug Deliv Rev 2002;54:1311–31.

Klintmalm G , Sawe J. High dose mefhylprednisolone increases plasma cyclosporin levels in renal transplant recipients (letter). Lancet 1984;1:731.

Huisman RM , van Son WJ , Tegzess AM . Interaction of intravenous methylprednisolone with oral CsA. Nephrol Dial Transplant 1990;5:905–6.

Hall TG . Effect of methylprednisolone on cyclosporine blood levels (abstract). Pharmacotherapy 1990;10:248.

Ptachcinski RJ , Venkataramanan R , Burckart GJ . Cyclosporine-high-dose steroid interaction in renal transplant recipients: assessment by HPLC. Transplant Proc 1987;19:1728–9.

Ubhi CS , Woodhouse L , Giles GR . Interaction of intravenous methylprednisolone with oral cyclosporin. Nephrol Dial Transplant 1990;5:376–8.

Cattaneo D , Perico N , Gaspari F , Gotti E , Remuzzi G. Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation. Kidney Int 2002;62:1060–7. DOI 10.1046/j.1523-1755.2002.00531.x

Kuypers DR , Claes K , Evenepoel P. Long-term changes in mycophenolic acid exposure in combination with tacrolimus and corticosteroids are dose dependent and not reflected by trough plasma concentration: a prospective study in 100 de novo renal allograft recipients. J Clin Pharmacol 2003;43:866–80.

Backman L , Kreis H , Morales JM , Wilczek H , Taylor R , Burke JT . Sirolimus steady-state trough concentrations are not affected by bolus methylprednisolone therapy in renal allograft recipients. Br J Clin Pharmacol 2002;54:65–8. DOI 10.1046/j.1365-2125.2002.01594.x

van Duijnhoven EM , Boots JM , Christiaans MH , Stolk LM , Undre NA , van Hooff JP . Increase in tacrolimus trough levels after steroid withdrawal. Transpl Int 2003;16:721–5. DOI 10.1007/s00147-003-0615-1

Anglicheau D , Flamant M , Schlageter MH . Pharmacokinetic interaction between corticosteroids and tacrolimus after renal transplantation. Nephrol Dial Transplant 2003;18:2409–14.

Gotti E , Perico N , Perna A. Renal transplantation: can we reduce calcineurin inhibitor/stop steroids? Evidence based on protocol biopsy findings. J Am Soc Nephrol 2003;14:755–66.

Langhoff E , Madsen S , Flachs H , Olgaard K , Ladefoged J , Hvidberg EF . Inhibition of prednisolone metabolism by cyclosporine in kidney-transplanted patients. Transplantation 1985;39:107–9.

Ost L. Effects of cyclosporin on prednisolone metabolism (letter). Lancet 1984;1:451.

Gregoor PJ , de Sevaux RG , Hene RJ . Effect of cyclosporine on mycophenolic acid trough levels in kidney transplant recipients. Transplantation 1999;68:1603–6.

Jusko WJ , Ferron GM , Mis SM , Kahan BD , Zimmerman JJ . Pharmacokinetics of prednisolone during administration of sirolimus in patients with renal transplants. J Clin Pharmacol 1996;36:1100–6.

Shimada T , Terada A , Yokogawa K. Lowered blood concentration of tacrolimus and its recovery with changes in expression of CYP3A and P-glycoprotein after high-dose steroid therapy. Transplantation 2002;74:1419–24. DOI 10.1097/01.TP.0000038287.39271.8F

Budde K , Geissler S , Hallebach G. Prospective randomized pilot study of steroid withdrawal with mycophenolate mofetil in long-term cyclosporine-treated patients: 4-year follow-up. Transplant Proc 2002;34:1703–5. DOI S0041134502029901

Jeng S , Chanchairujira T , Jusko W , Steiner R. Prednisone metabolism in recipients of kidney or liver transplants and in lung recipients receiving ketoconazole. Transplantation 2003;75:792–5. DOI 10.1097/01.TP.0000055099.97542.5D

Ali Shah I , Whiting PH , Omar G , Thomson AW , Burke MD . Effects of FK 506 on human hepatic microsomal cytochrome P-450–dependent drug metabolism in vitro. Transplant Proc 1991;23:2783–5.

Moochhala SM , Lee EJ , Earnest L , Wong JY , Ngoi SS . Inhibition of drug metabolism in rat and human liver microsomes by FK 506 and cyclosporine. Transplant Proc 1991;23:2786–8.

Piekoszewski W , Chow FS , Jusko WJ . Pharmacokinetic and pharmacodynamic effects of coadministration of methylprednisolone and tacrolimus in rabbits. J Pharmacol Exp Ther 1994;269:103–9.

van Gelder T. Drug interactions with tacrolimus. Drug Saf 2002;25:707–12.

Lampen A , Christians U , Guengerich FP . Metabolism of the immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability. Drug Metab Dispos 1995;23:1315–24.

Yokogawa K , Takahashi M , Tamai I. P-glycoprotein-dependent disposition kinetics of tacrolimus: studies in mdrla knockout mice. Pharm Res 1999;16:1213–8.

Nawrocki A , Korecka M , Solari S , Kang J , Shaw LM . Mycophenolic acid. In: Burton ME , Shaw LM , Schentag JJ , Evans WE , eds. Applied pharmacokinetics & pharmacodynamics. Principles of therapeutic drug monitoring. 4th ed. Baltimore: Lippincott Williams & Wilkins, 2006: 563–94.

Mahalati K , Kahan BD . Clinical pharmacokinetics of sirolimus. Clin Pharmacokinet 2001;40:573–85.

Cattaneo D , Merlini S , Pellegrino M. Therapeutic drag monitoring of sirolimus: effect of concomitant immunosuppressive therapy and optimization of drug dosing. Am J Transplant 2004;4:1345–51. DOI 10.1111/j.1600-6143.2004.00517.x

Donnenberg VS , Burckart GJ , Griffith BP , Jain AB , Zeevi A , Berg AD . P-Glycoprotein (P-gp) is upregulated in peripheral T-cell subsets from solid organ transplant recipients. J Clin Pharmacol 2001;41:1271–9.

Thorn M , Lundgren S , Herlenius G , Ericzon BG , Loof L , Rane A. Gene expression of cytochromes P450 in liver transplants over time. Eur J Clin Pharmacol 2004;60:413–20. DOI 10.1007/s00228-004-0786-4

Holt DW , Armstrong VW , Griesmacher A. International Federation of Clinical Chemistry/International Association of Therapeutic Drug Monitoring and Clinical Toxicology Working Group on Immunosuppressive Drug Monitoring. Ther Drug Monit 2002;24:59–67.

Oellerich M , Armstrong VW . The role of therapeutic drug monitoring in individualizing immunosuppressive drug therapy: recent developments. Ther Drug Monit 2006;28:720–5. DOI 10.1097/FTD.0b013e31802c5cf5