European Journal of Clinical Pharmacology

, Volume 43, Issue 2, pp 161–165 | Cite as

Pharmacokinetics of cyclosporine in hyperlipidaemic long-term survivors of heart transplantation

Lack of interaction with the lipid-lowering agent, fenofibrate
  • M. deLorgeril
  • P. Boissonnat
  • C. A. Bizollon
  • J. Guidollet
  • G. Faucon
  • J. P. Guichard
  • R. Levy-Prades-Sauron
  • S. Renaud
  • G. Dureau


Cyclosporine (Cy) binds to lipoproteins in plasma. In order to test if its pharmacokinetics would be modified when efficient lipid-lowering treatment is introduced, a study has been done of Cy pharmacokinetics and any interaction with the lipid-lowering agent fenofibrate in hyperlipidaemic long-term, survivors of heart transplantation. Fenofibrate 200 mg once daily significantly reduced blood lipids (cholesterol 6.5 vs 7.7 mmol/l; apoprotein B 1.2 vs 1.6 g/l) but did not modify mean whole blood Cy trough levels (113 before fenofibrate vs 103 ng·ml−1), Cmax (812 ng·ml−1 by RIA and 757 ng·ml−1 by HPLC before fenofibrate versus 865 and 741 respectively, during fenofibrate); tmax (1.6 and 1.7 h before fenofibrate versus 1.4 and 1.4 h respectively), and t1/2 (13.9 and 11.1 h versus 9.5 and 10.7 h).

The only adverse effect was an increase in creatinine (157 vs 145 mmol/l). Further studies are needed to investigate the mechanism of Cy-fenofibrate nephrotoxicity and to evaluate the long-term efficiency and safety of fenofibrate after heart transplantation.

Key words

Cyclosporine Hyperlipidaemia heart transplantation fenofibrate fenofibric acid pharmacokinetics drug interaction nephrotoxicity 


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  1. 1.
    Billingham ME (1987) Cardiac transplant atherosclerosis. Transplant Proc 19: 19–25PubMedGoogle Scholar
  2. 2.
    Stamler JS, Vaughan DE, Rudd A, Mudge GH, Kirshenbaum J, Young P, Alexander RW, Loscalzo J (1988) Frequency of hypercholesterolemia after cardiac transplantation. Am J Cardiol 62: 1268–1272PubMedGoogle Scholar
  3. 3.
    Rudas L, Pflugfelder PW, McKenzie N, Menkis AH, Novick RJ, Kostuk WJ (1990) Serial evaluation of lipid profiles and risk factors for development of hyperlipidemia after cardiac transplantation. Am J Cardiol 66: 1135–1138PubMedGoogle Scholar
  4. 4.
    Ballantyne CM, Podet EJ, Patsch WP, Harati Y, Appel V, Gotto AM, Young JB (1989) Effects of cyclosporine therapy on plasma lipoprotein levels. JAMA 262: 53–56PubMedGoogle Scholar
  5. 5.
    Jevnikar AM, Petric R, Holub BJ, Philbrick DJ, Clark WF (1988) Effect of cyclosporine on plasma lipids and modification with dietary fish oil. Transplantation 46: 722–725PubMedGoogle Scholar
  6. 6.
    Ettinger WH, Dysko RC, Clarkson TB (1989) Prednisone increases low density lipoprotein in cynomolgus monkeys fed saturated fat and cholesterol. Arteriosclerosis 9: 848–855PubMedGoogle Scholar
  7. 7.
    De Lorgeril M, Dureau G, Guidollet J, Boissonnat P, Renaud S (1990) Prevalence of dyslipidemia in long-term survivors of heart transplantation. Eur Heart J 11: 176Google Scholar
  8. 8.
    Ryffel B, Donatsch P, Madörin M, Matter BE, Rüttimann G, Schön H, Stoll R, Wilson J (1983) Toxicological evaluation of cyclosporin A. Arch Toxicol 53: 107–141PubMedGoogle Scholar
  9. 9.
    Kahan BD (1989) Cyclosporine. New Engl J Med 321: 1725–1738PubMedGoogle Scholar
  10. 10.
    Lemaire M, Tillement JP (1982) Role of lipoproteins and erythrocytes in the in vitro binding and distribution of cyclosporin A in the blood. J Pharmacol 34: 715–718Google Scholar
  11. 11.
    Knopp RH, Walden CE, Warnick GR, Albers JJ, Ginsberg J, McGinnis BM (1987) Effects of fenofibrate treatment on plasma lipoprotein lipids, high-density lipoprotein cholesterol subfractions, and apolipoproteins B, AI, AII, and E. Am J Med 83: 75–84PubMedGoogle Scholar
  12. 12.
    Brown WV, Dujovne CA, Farquhar JW, Feldman EB, Grundy SM, Knopp RH, Lasser NL, Mellies MJ, Palmer RH, Samuel P, Schonfeld G, Superko HR (1986) Effects of fenofibrate on plasma lipids. Double-blind, multicenter study in patients with type IIA or IIB hyperlipidemia. Arteriosclerosis 6: 670–678PubMedGoogle Scholar
  13. 13.
    Bizollon CA, Cohen R (1990) French interlaboratory cyclosporine quality assesment scheme. Nucl Med Biol 17: 737–744Google Scholar
  14. 14.
    Ball PE, Munzer H, Keller HP, Abisch E, Rosenthaler J (1988) Specific H Radioimmunoassay with a monoclonal antibody for monotoring cyclosporine in blood. Clin Chem 34: 257–261PubMedGoogle Scholar
  15. 15.
    Garaffo R, Lapalus P (1985) Simplified liquid chromatographic analysis for cyclosporine A in blood and plasma with use of rapid extraction. J Chromatogr 337: 416–422PubMedGoogle Scholar
  16. 16.
    Aronson JK, Dengler HJ, Dettli L, Follath F (1988) Editorial: standardization of symbols in clinical pharmacology. Eur J Clin Pharmacol 35: 1–7PubMedGoogle Scholar
  17. 17.
    Kahan BD (1985) Individualization of cyclosporine therapy using pharmacokinetic and pharmacodynamic parameters. Transplantation 40: 457–476PubMedGoogle Scholar
  18. 18.
    Critical issues in cyclosporine monitoring: report of the task force on cyclosporine monitoring (1987) Clin Chem 33: 1269–1288Google Scholar
  19. 19.
    Venkataramanan R, Burckart GJ, Ptachcinski RJ, Lee A, Hardesty RL, Griffith BP (1986) Cyclosporine pharmacokinetics in heart transplant recipients. Transplant Proc 4: 768–770Google Scholar
  20. 20.
    Brockmöller J, Neumayer HH, Wagner K, Weber W, Heinemeyer G, Kewitz H, Roots I (1990) Pharmacokinetic interaction between cyclosporin and diltiazem. Eur J Clin Pharmacol 38: 237–242PubMedGoogle Scholar
  21. 21.
    Lindholm A, Henricsson S, Gang P (1988) The free fraction of cyclosporine in plasma: clinical findings with a new method. Transplant Proc 20: 377–381Google Scholar
  22. 22.
    Freed BM, Rosano TG, Lempert N (1987) In vitro immunosuppressive properties of cyclosporine metabolites. Transplantation 43: 123–127PubMedGoogle Scholar
  23. 23.
    Kunzendorf U, Brockmöller J, Jochimsen F, Roots I, Offermann G (1989) Immunosuppressive properties of cyclosporine metabolites. Lancet 1: 734–735Google Scholar
  24. 24.
    Rössenr S, Orö L (1981) Fenofibrate therapy of hyperlipoproteinaemia. A dose-response study and a comparison with clofibrate. Atherosclerosis 38: 273–282PubMedGoogle Scholar
  25. 25.
    Kobashigawa JA, Murphy FL, Stevenson LW et al. (1990) Lowdose lovastatin safely lowers cholesterol after cardiac transplantation. Circulation 82 [Suppl IV]: IV 281-IV 283Google Scholar
  26. 26.
    De Groen PC, Wiesner RH, Krom RAF (1988) Cyclosporine Ainduced side effects related to a low total serum cholesterol level: an indication for a free cyclosporine A assay? Transplant Proc 20: 374–376PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • M. deLorgeril
    • 1
    • 6
  • P. Boissonnat
    • 1
  • C. A. Bizollon
    • 2
  • J. Guidollet
    • 3
  • G. Faucon
    • 4
  • J. P. Guichard
    • 5
  • R. Levy-Prades-Sauron
    • 5
  • S. Renaud
    • 1
  • G. Dureau
    • 1
  1. 1.INSERM, U 63DaixFrance
  2. 2.Service de Radiopharmacie et RadioanalyseCentre de Médecine NucléaireDaixFrance
  3. 3.Laboratory of BiochemistryHôpital CardiologiqueDaixFrance
  4. 4.Laboratory of Clinical PharmacologyHôpital E. HerriotDaixFrance
  5. 5.Fournier Research CentreDaixFrance
  6. 6.INSERM U 63BronFrance

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