Skip to main content
SpringerLink
Log in

Die Pharmakokinetik von Adriamycin und Adriamycin-Metaboliten

The pharmacokinetics of adriamycin and adriamycin-metabolites

  • Originalien
  • Published:
Klinische Wochenschrift Aims and scope Submit manuscript

Summary

A sensitive reproducible, nondestructive method for the determination of adriamycin and its' metabolites in plasma, leukocytes and tissues has been developed. Apolar substances as adriamycinone (adm-one) were extracted at pH 2 with chloroform, polar ones as adriamycin (adm) and adriamycinol (adm-ol) at pH 8.8 with chloroform: methanol, separated by thin-layer-chromatography and quantitated by fluorescence spectrophotometry.

The plasma levels of adm-ol and adm-one were lower in all patients compared to those of adm. Further metabolites were found in the bile. Toxic effects were found in patients with prolonged half-lives in the elimination phase. A delayed elimination was observed in a patient with an elevation of the bilirubin level, but also in patients without overt liver disease. The pharmacokinetics of adm showed considerable inter- and intraindividual fluctuations.

Zusammenfassung

Eine empfindliche, reproduzierbare, nichtdestruktive Methode für die Bestimmung von Adriamycin und seinen Metaboliten in Plasma, Leukozyten und Geweben wurde entwickelt. Apolare Substanzen wie Adriamycin (Adm-on) wurden bei pH 2 mit Chloroform, polare wie Adriamycin (Adm) und Adriamycinol (Adm-ol) bei pH 8.8 mit Chloroform:Methanol extrahiert. Nach einer Dünnschichtchromatographie wurde spektrophotofluorometrisch quantifiziert.

Bei allen untersuchten Patienten überwog im Plasma Adm über Adm-ol und Adm-on. Weitere Metaboliten fanden sich im Gallensaft. Ausgeprägte Nebenwirkungen traten bei Patienten mit verlängerten Halbwertszeiten der Elimination auf. Eine verzögerte Elimination wurde bei einer Patientin mit Bilirubinerhöhung aber auch bei Patienten ohne erkennbare Lebererkrankung beobachtet. Die Pharmakokinetik von Adm zeigte erhebliche inter- und intraindividuelle Schwankungen.

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

Access this article

Log in via an institution

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

Literatur

  1. Arena E, d'Alessandro N, Dusonchet L, Gebbia N, Gerbasi F, Palazzoadriano M, Raineri A, Rausa L, Tubaro E (1971) Analysis of the pharmacokinetic characteristics, pharmacological and chemotherapeutic activity of 14-hydroxydaunomycin (adriamycin), a new drug endowed with an antitumor activity. Arzneim Forsch 21:1258–1263

    Google Scholar 

  2. Asbell MA, Schwartzbach E, Bullock FJ, Yesair DW (1972) Daunomycin and adriamycin metabolism via reductive glycosidic cleavage. J Pharmacol Exp Ther 182:63–69

    Google Scholar 

  3. Bachur NR, Huffman DH (1971) Daunorubicin metabolism: estimation of daunorubicin reductase. Br J Pharmacol 43:828–833

    Google Scholar 

  4. Bachur NR, Hildebrand RC, Jaenke RS (1974) Adriamycin and daunomycin disposition in the rabbit. J Pharmacol Exp Ther 191:331–340

    Google Scholar 

  5. Bachur NR, Riggs CE, Green MR, Lagone JJ, Van Vunakis H, Levine L (1976) Plasma adriamycin and daunomycin levels by fluorescence and radioimmunoassay. Clin Pharmacol Ther 21:70–77

    Google Scholar 

  6. Baker LH, Saiki JH, Jones SH, Hewlett JS, Bronlee RW, Stephens RL, Vaitkevicius VK (1977) Adriamycin and 5-fluorouracil in the treatment of advanced hepatoma: A southwest oncology group study. Cancer Treat Rep 61:1595–1597

    Google Scholar 

  7. Benjamin RS, Riggs CE, Bachur NR (1973) Pharmacokinetics and metabolism of adriamycin in man. Clin Pharmacol Ther 14:592–600

    Google Scholar 

  8. Benjamin RS, Wiernik PH, Bachur NR (1974) Adriamycin chemotherapy-efficacy, safety and pharmacologic basis of an intermittent single high dosage schedule. Cancer 33:19–27

    Google Scholar 

  9. Benjamin RS, Riggs CE, Serpick AA, Bachur NR (1974) Human metabolism of adriamycin. Proc Am Assoc Cancer Res 15:76

    Google Scholar 

  10. Benjamin RS (1975) Clinical pharmacology of adriamycin. Cancer Chemother Rep 6:183–185

    Google Scholar 

  11. Benjamin RS, Riggs CE, Bachur NR (1977) Plasma pharmacokinetics of adriamycin and its metabolites in humans with normal hepatic and renal function. Cancer Res 37:1416–1420

    Google Scholar 

  12. Böyum A (1968) Separation of leucocytes from blood and bone marrow. Scand J Clin Lab Invest 21 [Suppl. 97]

  13. Bonadonna G, Monfardini S, De Lena M (1972) Clinical trials with adriamycin. Results of a three years study. In: Carter SK, DiMarco A, Ghione M, et al. (eds) International Symposium on Adriamycin. Springer, Berlin Heidelberg New York, pp 139–152

    Google Scholar 

  14. Bullock FJ, Bruni RJ, Asbell MA (1972) Identification of new metabolites of daunomycin and adriamycin. J Pharmacol Exp Ther 182:70–76

    Google Scholar 

  15. Carter SK (1975) Adriamycin- a review. J Natl Cancer Inst 55:1265–1274

    Google Scholar 

  16. Chan KK, Harris PhA (1973) A fluorometric determination of adriamycin and its metabolites in biological tissues. Res Commun Chem Pathol Pharmacol 6:447–463

    Google Scholar 

  17. Chan KK, Sakai JL (1979) Pharmacokinetics of adriamycinol (NSC-268238) in rabbits. Proc Am Assoc Cancer Res 20:1040

    Google Scholar 

  18. Chan KK, Cohen JL, Gross JF, Himmelstein KJ, Bateman JR, Yeu Tsu-Lee, Marlis AS (1978) Prediction of adriamycin disposition in cancer patients using a physiologic, pharmacokinetic model. Cancer Treat Rep 62:1161–1171

    Google Scholar 

  19. Cradock JC, Egorin MJ, Bachur NR (1973) Daunorubicin biliary excretion and metabolism in the rat. Arch Int Pharmacodyn Ther 202:48–61

    Google Scholar 

  20. Creasey WA, McIntosh LS, Brescia T, Odujinrin O, Aspnes GT, Murray E, Marsh JC (1976) Clinical effects and pharmacokinetics of different dosage schedules of adriamycin. Cancer Res 36:216–221

    Google Scholar 

  21. Di Fronzo G, Lenaz L, Bonadonna G (1973) Distribution and excretion of adriamycin in man. Biomedicine 19:169–171

    Google Scholar 

  22. Di Marco A, Zunino F, Silvestrini F (1971) Interaction of some daunomycin derivates with deoxyribonucleic acid and their biological activity. Biochem Pharmacol 20:1323–1328

    Google Scholar 

  23. Henderson C, Frei E (1979) Adriamycin and the heart. New Engl J Med 300:310–311

    Google Scholar 

  24. Kim SH, Kim JH (1972) Lethal effect of adriamycin on the division cycle of HeLa cells. Cancer Res 32:323–325

    Google Scholar 

  25. Reich SD, Steinberg F, Bachur NR, Riggs CE, Goebel R, Berman M (1979) Mathematical model for adriamycin (doxorubicin) pharmacokinetics. Cancer Chemother Pharmacol 3:125–131

    Google Scholar 

  26. Riggs CF, Benjamin RS, Serpick AA, Bachur NR (1977) Biliary disposition of adriamycin. Clin Pharmacol Therap 22:234–241

    Google Scholar 

  27. Rosenoff SH, Brooks E, Bostick F, DeVita VT, Young RC (1974) Alterations of DNA-synthesis in heart, bone marrow and G.I. mucosa induced by adriamycin in vivo: relationship to fatal toxicity. Proc Am Assoc Cancer Res 15:38

    Google Scholar 

  28. Rosso R, Ravanzzoni C, Esposito M, Sala R, Santi L (1972) Plasma and urinary levels of adriamycin in man. Eur J Cancer 8:455–459

    Google Scholar 

  29. Schwartz HS (1973) A fluorometric assay for daunomycin in animal tissues. Biochem Med 7:396–404

    Google Scholar 

  30. Takanashi S, Bachur NR (1976) Adriamycin metabolism in man, evidence from urinary metabolites. Drug Metab Dispos 4:79–87

    Google Scholar 

  31. Vogel CL, Bayley AC, Brooker RJ, Anthony PP, Ziegler JL (1977) A phase II study of adriamycin (NSC 123127) in patients with hepatocellular carcinoma from Zambia and the United States. Cancer 39:1923–1929

    Google Scholar 

  32. Watson E, Chan K (1976) Rapid analytic method for adriamycin and metabolities in human plasma by a thin-film fluorescence scanner. Cancer Treat Rep 60:1611–1618

    Google Scholar 

  33. Weiss AJ, Manthel RW (1977) Experience with the use of adriamycin in combination with other anticancer agents using a weekly schedule, with particular reference to lack of cardiac toxicity. Cancer 40:2046–2052

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Abteilung Innere Medizin II, Medizinische Universitätsklinik, Tübingen

    G. Ehninger, H. J. Stocker, B. Proksch & K. Wilms

Authors
  1. G. Ehninger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. J. Stocker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Proksch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. Wilms
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ehninger, G., Stocker, H.J., Proksch, B. et al. Die Pharmakokinetik von Adriamycin und Adriamycin-Metaboliten. Klin Wochenschr 58, 927–934 (1980). https://doi.org/10.1007/BF01477050

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01477050

Key words

Schlüsselwörter

Search

Navigation