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Ciclosporin metabolite pattern in blood and urine of liver graft recipients

I. Association of ciclosporin metabolites with nephrotoxicity

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Summary

Blood ciclosporin (Cs) metabolite pattern in 58 liver grafted patients was routinely monitored by HPLC from the first Cs dose after transplantation until discharge from hospital. Eighteen patients with normal kidney function were allocated to Group I and 14 patients in Group II suffered Cs nephrotoxicity during their clinical course.

There were no significant differences between both groups in blood Cs level, kidney function before transplantation, liver function or co-administration of other potentially nephrotoxic drugs. A correlation matrix involving both groups showed a significant correlation between the blood concentration of metabolite M1c9 and serum creatinine and urea, and an inverse correlation with creatinine clearance. During a nephrotoxic episode the blood concentrations of metabolites M1c9 and M1A were significantly elevated in patients in Group II. Analysis of the time course revealed significantly higher blood levels of M19 and M1c9 in Group II patients compared with those in Group I for the first 10 days after transplantation. Serum creatinine and urea concentrations remained significantly elevated, the creatinine clearance being significantly reduced throughout the period of observation.

The elevated blood concentrations of ciclosporin metabolites M1c9 and M19 during nephrotoxic episodes suggest that these metabolites are associated with ciclosporin nephrotoxicity. It could not be decided if the elevated metabolite concentrations were the result of and/or the reason for impaired kidney function.

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References

  1. Wallemacq PE, Lhoëst G, Dumont P (1989) Isolation, purification and structure elucidation of cyclosporine metabolites in rabbit and man. Biomed Environ Mass Spectrom 18: 48–56

    Google Scholar 

  2. Maurer G, Loosli R, Schreier E, Keller H (1984) Disposition of cyclosporine in several animal species and man-structural elucidation of its metabolites. Drug Metab Dispos 12: 120–126

    Google Scholar 

  3. Maurer G, Lemaire M (1986) Biotransformation of cyclosporine and distribution in blood. Transplant Proc 18: 25–34

    Google Scholar 

  4. Hartmann NR, Jardine I (1986) Mass spectrometric analysis of cyclosporine metabolites. Biomed Environ Mass Spectrom 13: 361–372

    Google Scholar 

  5. Kunzendorf U, Brockmöller J, Joachimsen F, Keller F, Walz G, Offermann G (1988) Cyclosporine metabolites and central-nervous-system toxicity Lancet I: 1223

    Google Scholar 

  6. Davenport A, Will EJ, Davison AM, Ironside JW (1988) Toxicity of cyclosporine metabolites. Lancet II: 333

    Google Scholar 

  7. Rosano TG, Pell MA, Freed BM, Dybas MT, Lempert N (1988) Cyclosporine and metabolites in blood from renal allograft recipients with nephrotoxicity, rejection, or good renal function: comparative high-performance liquid chromatography and monoclonal radioimmunoassay studies. Transplant Proc 20: 330–338

    Google Scholar 

  8. Leunissen K, Baumann G, Bosman R, Van Hoof JP (1986) Cyclosporin metabolites and nephrotoxicity. Lancet II: 1398

    Google Scholar 

  9. Ryffel B, Foxwell BMJ, Mihatsch MJ, Donatsch P, Maurer G (1988) Biological significance of cyclosporine metabolites. Transplant Proc 20: 575–584

    Google Scholar 

  10. Donatsch P, Rickenberger U, Ryffel B, Brouillard JF, Tschopp M, Wullschleger J (1990) Adverse reaction profiles of Sandimmune (CsA) metabolites. Transplant Proc 22 (3): 1137–1140

    Google Scholar 

  11. Christians U, Sewing KF (1989) Whole blood sample clean-up for chromatographic analysis. In: Zech K, Frei RW (eds) Selective sample handling and detection in high-performance liquid chromatography, Part B. Elsevier, Amsterdam, pp 82–132

    Google Scholar 

  12. Wonigeit K, Kohlhaw K, Winkler M, Schaefer O, Pichlmayr R (1990) Cyclosporine monitoring in liver allograft recipients. Two distinct patterns of blood level derangement associated with nephrotoxicity. Transplant Proc 22 (3): 1305–1311

    Google Scholar 

  13. Christians U, Zimmer KO, Wonigeit K, Sewing KF (1987) Measurement of cyclosporin A and four of its metabolites in whole blood by high-performance liquid chromatography. J Chromatogr 413: 121–129

    Google Scholar 

  14. Christians U, Zimmer KO, Wonigeit K, Maurer G, Sewing KF (1988) Liquid chromatographic measurement of cyclosporin A and its metabolites in blood, bile, and urine. Clin Chem 34: 34–39

    Google Scholar 

  15. Sewing KF, Christians U, Bleck JS, Schottmann R, Strohmeyer SS (1988) Measurement and disposition of cyclosporine and its metabolites. Bibliotheca Cardiol 43: 63–72

    Google Scholar 

  16. Kahan BD (1990) Consensus report of the ciclosporin expert meeting, Hawk's Cay, 1990. Transplant Proc 22 (3): 1357–1361

    Google Scholar 

  17. Wadhwa NK, Schroeder TJ, Amadeo JP, Myre SA, Clardy SW, First MR (1987) Cyclosporine drug interactions: a review. Ther Drug Monit 9: 399–406

    Google Scholar 

  18. Cockburn ITR, Krupp P (1989) An appraisal of drug interactions with SandimmunR. Transplant Proc 21: 3845–3850

    Google Scholar 

  19. Racusen LC, Solez K (1988) Cyclosporine nephrotoxicity. Int Rev Exp Pathol 30: 107–157

    Google Scholar 

  20. Mason J (1989) Pharmacology of cyclosporine (Sandimmune) VII. Pathophysiology and toxicology of cyclosporine in humans and animals. Pharmacol Rev 42: 423–434

    Google Scholar 

  21. Kahan BD (1989) Cyclosporine. N Engl J Med 321: 1725–1738

    Google Scholar 

  22. Cole E, Cheung F, Wong PY, Fung LS, Skorecki K, Levy GA (1989) Toxic effects on renal cells in culture- a comparison of cyclosporin A and its metabolites. Transplant Proc 21: 943–945

    Google Scholar 

  23. Bouis P, Brouillard JF, Fischer V, Donatsch P, Boelsterli UA (1990) Effect of enzyme induction on Sandimmun (Cyclosporin A) biotransformation and hepatotoxicity in cultured rat hepatocytes and in vivo. Biochem Pharmacol 39: 257–266

    Google Scholar 

  24. Bowers LD (1990) Studies of cyclosporine and metabolite toxicity in renal and hepatocyte culture systems. Transplant Proc 22: 1135–1136

    Google Scholar 

  25. Bleck JS, Schlitt HJ, Christians U, Thiesemann C, Strohmeyer S, Schottmann R, Kohlhaw K, Wonigeit K, Sewing KF (1989) Urinary excretion of ciclosporin and 17 of its metabolites in renal allograft recipients. Pharmacol 39: 160–164

    Google Scholar 

  26. Mihatsch MJ, Steiner K, Abeywickrama KH, Landmann J, Thiel G (1988) Risk factors for the development of chronic cyclosporine-nephrotoxicity. Clin Nephrol 29: 165–175

    Google Scholar 

  27. Lucey MR, Kolars JC, Merion RM, Campbell DA, Aldrich M, Watkins PB (1990) Cyclosporin toxicity at therapeutic blood levels and cytochrome P-450 IIIA. Lancet 335: 11–15

    Google Scholar 

  28. Kohlhaw K, Wonigeit K, Schäfer O, Ringe B, Bunzendahl H, Pichlmayr R (1989) Association of very high blood levels of cyclosporine metabolites with clinical complications after liver transplantation. Transplant Proc 21: 2232–2233

    Google Scholar 

  29. Nagelkerke FJ, Tijdens RB, Schwarz EP, Winters MFG, Paul LC, Mulder GJ (1987) The covalent binding of cyclosporin A to rat liver macromolecules in vivo and in vitro: the role of cytochrome P450. Toxicology 40: 277–284

    Google Scholar 

  30. Christians U, Schlitt HJ, Bleck JS, Kownatzki R, Schiebel HM, Maurer G, Strohmeyer SS, Schottmann R, Wonigeit K, Pichlmayr R, Sewing KF (1988) Measurement of cyclosporine and 18 metabolites in blood, bile and urine by high performance liquid chromatography. Transplant Proc 20: 609–613

    Google Scholar 

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Christians, U., Kohlhaw, K., Budniak, J. et al. Ciclosporin metabolite pattern in blood and urine of liver graft recipients. Eur J Clin Pharmacol 41, 285–290 (1991). https://doi.org/10.1007/BF00314953

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