Cancer Chemotherapy and Pharmacology

, Volume 21, Issue 3, pp 221–228 | Cite as

Epirubicin and doxorubicin comparative metabolism and pharmacokinetics

A cross-over study
  • Carlo M. Camaggi
  • Raffaella Comparsi
  • Elena Strocchi
  • Fabio Testoni
  • Bruna Angelelli
  • Franco Pannuti
Original Articles Doxorubicin, Epirubicon, Metabolism, Pharmacokinetics


The pharmacokinetics and metabolism of doxorubicin (DX) and epirubicin (epiDX) were investigated in eight cancer patients who received 60 mg/m2 of both drugs independently by intravenous (i.v.) bolus at 3-week intervals according to a balanced cross-over design. Unchanged DX and epiDX plasma levels followed a triexponential decay. Half-lives (t/2) of the three decay phases were longer for DX (t/2α: 4.8 vs. 3 min; t/2β 2.57 h vs. 1.09 h; t/2γ 48.4 vs. 31.2 h). According to a model-independent analysis, the different plasma disposition kinetics of the two compounds appears to be related to a higher plasma clearance (PlCl) and to a lower mean residence time (MRT) of epiDX (PlCl: 75.0 l/h, range: 35.6–133.4 l/h; MRT: 31.6 h, range: 7.0–41.5 h;) compared to DX (PlCl: 56.8 l/h, range: 24.4–119.5; MRT: 45.6 h, range: 26.0–83.1 h). No statistically significant differences could be detected for the volume of distribution at steady state (Vss) (epiDX, 31.8 l/kg; DX, 33.3 l/kg). Metabolites common to both compounds were detected in plasma: the 13-dihydro derivatives doxorubicinol (DXol) and epirubicinol (epiDXol), together with monor amounts of four aglycones (7-deoxy adriamycinone, adriamycinone, 7-deoxy 13-dihydro adriamycinone, and 13-dihydro adriamycinone). Following epiDX administration, two additional major metabolites were detected: the glucuronic acid conjugates of epiDX (4′-O-β-d-glucuronyl-4′-epiDX) and epiDXol (4′-O-β-d-glucuronyl 13-dihydro-4′-epiDX). This additional detoxication route appears to account for the more efficient and faster elimination of epiDX than of DX. In the urine collected in the 6 days after treatment, 12.2% of the DX and 11.9% of the epiDX dose was excreted as unchanged drug and fluorescent metabolites. A comparable renal clearance was calculated for DX (4.7 l/h, range 1.4–7.0 l/h) and epiDX (4.4 l/h, range 1.7–7.0 l/h). One patient with hepatic metastates and abnormal bilirubin serum level had percutaneous biliary drainage because of extrahepatic obstruction. The elimination of both drugs was significantly impaired in this patient; nevertheless, elimination of epiDX was still more efficient and faster than that of DX (PlCl: 35.6 vs. 24.4 l/h; MRT: 39.0 vs. 83.1 h; t/2γ: 47 vs. 74 h). This patient's biliary excretion accounted for 35.4% of the epiDX dose and 18.2% of the DX dose.


Epirubicin Glucuronic Acid Mean Residence Time Percutaneous Biliary Drainage Glucuronic Acid Conjugate 
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  1. 1.
    Arcamone F, Penco S, Vigevani A, Redaelli S, Franchi G, DiMarco A, Casazza AM, Dasdia T, Formelli F, Necco A, Soranzo C (1975) Synthesis and antitumor properties of new glycosides of daunomycinone and adriamycinone. J Med Chem 18:703–707Google Scholar
  2. 2.
    Bonadonna G, Brambilla C, Rossi A, Bonfante V, Ferrari L, Villani F (1984) Epidoxorubicin in advanced breast cancer. The experience of the Milan Cancer Institute. In: Bonadonna G (ed) Advances in anthracycline chemotherapy: Epirubicin. Masson, Milan, pp 63–74Google Scholar
  3. 3.
    Brenner DE, Galloway S, Cooper J, Noone R, Hande KR (1985) Improved high-performance liquid chromatography assay of doxorubicin: Detection of circulating aglycones in human plasma and comparison with thin-layer chromatography. Cancer Chemother Pharmacol 14:139–145Google Scholar
  4. 4.
    Camaggi CM, Strocchi E, Tamassia V, Martoni A, Giovannini M, Iafelice G, Canova N, Marraro D, Martini A, Pannuti F (1982) Pharmacokinetic studies of 4′-epidoxorubicin in cancer patients with normal and impaired renal functions and with hepatic metastases. Cancer Treat Rep 66:1819–1824Google Scholar
  5. 5.
    Camaggi CM, Strocchi E, Martoni A, Angelelli B, Comparsi R, Pannuti F (1985) Epirubicin plasma and blood pharmacokinetics after single IV bolus in advanced cancer patients. Drugs Exp Clin Res 11:285–294Google Scholar
  6. 6.
    Camaggi CM, Comparsi R, Strocchi E, Testoni F, Pannuti F (1988) HPLC analysis of doxorubicin, epirubicin and fluorescent metabolites in biological fluids. Cancer Chemother Pharmacol 21:216–220Google Scholar
  7. 7.
    Cassinelli G, Configliacchi E, Penco S, Rivola G, Arcamone F, Pacciarini A, Ferrari L (1984) Separation, characterization and analysis of epirubicin (4′-epidoxorubicin) and its metabolites from human urine. Drug Metab Dispos 12:4–20Google Scholar
  8. 8.
    Chan KK, Chlebowski RT, Tong M, Chen HSG, Gross JF, Bateman JR (1980) Clinical pharmacokinetics of adriamycin in hepatoma patients with cirrhosis. Cancer Res 40: 1263–1268Google Scholar
  9. 9.
    Dixon WJ, Brown MB (1979) BMDP-79 biomedical computer programs, P-series. University of California Press, BerkeleyGoogle Scholar
  10. 10.
    Ganzina F (1979) 4′-epidoxorubicin, a new analogue of doxorubicin: a preliminary overview of preclinical and clinical data. Cancer Treat Rev 10:1–22Google Scholar
  11. 11.
    Gibaldi G, Perrier D (1982) Pharmacokinetics, 2nd edn. Marcel Dekker, New YorkGoogle Scholar
  12. 12.
    Jain KK, Casper ES, Geller NL, Hakes TB, Kaufmann RJ, Currie V, Schwartz W, Cassidy C, Petroni Gr, Young CW, Wittes RE (1985) A proespective randomized comparison of doxorubicin and a less cardiotoxic analog epirubicin in patients with advanced breast cancer. J Clin Oncol 3:818–824Google Scholar
  13. 13.
    Martini A, Moro E, Pacciarini MA, Tamassia V, Natale N, Piazza E (1984) Crossover study of pharmacokinetics and haematological toxicity of 4′-epi-doxorubicin and doxorubicin in cancer patients. Int J Clin Pharmacol Res 4:231–238Google Scholar
  14. 14.
    Robert J, Vrignaud P, Nguyen-Ngoc T, Iliadis A, Mauriac L, Hurteloup P (1985) Comparative pharmacokinetics and metabolism of doxorubicin and epirubicin in patients with metastatic breast cancer. Cancer Treat Rep 69:633–640Google Scholar
  15. 15.
    Weenen H, Lenkelma JP, Penders PGM, McVie JG, Ten Bokkel Huinink WW, De Planque MM, Pinedo HM (1983) Pharmacokinetics of 4′-epi-doxorubicin in man. Invest New Drugs 1:59–64Google Scholar
  16. 16.
    Young CW (1984) Epirubicin: a therapeutically active doxorubicin analogue with reduced cardiotoxicity. In: Bonadonna G (ed) Advances in anthracycline chemotherapy: Epirubicin. Masson, Milan, pp 183–188Google Scholar

Copyright information

© Springer-Verlag 1988

Authors and Affiliations

  • Carlo M. Camaggi
    • 1
  • Raffaella Comparsi
    • 1
  • Elena Strocchi
    • 2
  • Fabio Testoni
    • 1
  • Bruna Angelelli
  • Franco Pannuti
  1. 1.Dipartimento di Chimica Organica dell'Universita'BolognaItaly
  2. 2.Divisione di OncologiaOspedale M. MalpighiBolognaItaly

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