Pharmaceutisch Weekblad

, Volume 10, Issue 5, pp 200–206 | Cite as

Pharmacokinėtics of intravenous and oral cyclophosphamide in the presence of methotrexate and fluorouracil

  • E. A. De Bruijn
  • P. H. TH. J Slee
  • A. T. Van Oosterom
  • D. W. Lameijer
  • K. J. Roozendaal
  • U. R. Tjaden
Original Articles


Cyclophosphamide was administered to 12 breast cancer patients in combination with methotrexate and fluorouracil. Doses prescribed were cyclophosphamide 75 mg/m2, methotrexate 30 mg/m2 and fluorouracil 500 mg/m2 (per square meter body surface). Cyclophosphamide was administered intravenously and orally in aqueous solutions and in tablets in a randomized cross-over trial. Methotrexate and fluorouracil were administered intravenously, methotrexate was given first and then fluorouracil. Assays of cyclophosphamide in blood plasma were performed by capillary gas chromatography. Data of mean bioavailability of cyclophosphamide administered by tablets were suggestive of sufficient absorption. In 2 patients, however, a lower bioavailability of cyclophosphamide was demonstrated. Intra-individual differences in the terminal slope of the plasma decay curves after intravenous and oral administration in some patients decreased the calculated bioavailability of cyclophosphamide, if these values were included in the calculation of cyclophosphamide bioavailability. Compared with the administration of the solutions peak times, lag-times and mean absorption times of cyclophosphamide given in tablets were markedly prolonged. It is concluded that interactions between cyclophosphamide and methotrexate and/or fluorouracil after oral dosing as tablets are different from interactions observed after intravenous administration of cyclophosphamide.


Administration, intravenous Administration, oral Biological availability Clinical trials Cyclophosphamide Drug interactions Fluorouracil Methotrexate Pharmacokinetics 


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  1. 1.
    Hill DL. A review of cyclophosphamide. Springfield: Charles C. Thomas, 1975:3–340.Google Scholar
  2. 2.
    Cox PJ, Farmer PB, Jarman M, eds. Symposium on the metabolism and mechanism of action of cyclophosphamide. Cancer Treat Rep 1976:299–525.Google Scholar
  3. 3.
    Brock N, Hohorst H-J. The problem of specificity and selectivity of alkylating cytostatics: studies onN-2-chloroethylamido-oxaza-phosphorines. Z Krebsforsch Klin Onkol 1977:185–215.Google Scholar
  4. 4.
    Friedman OM, Myles A, Colvin M. Cyclophosphamide and related phosphoramide mustards. Current status and future prospects. Adv Cancer Chemother 1979:143–204.Google Scholar
  5. 5.
    Colvin M, Hilton J. Pharmacology of cyclophosphamide and metabolites. Cancer Treat Rep 1981;65(suppl 3):89–95.Google Scholar
  6. 6.
    Grochow LB, Colvin M. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 1980;380–94.Google Scholar
  7. 7.
    D'Incalci M, Bolis G, Fachinetti T, et al. Decreased half life of cyclophosphamide in patients under continuous treatment. Eur J Cancer 1979;15:7–10.PubMedGoogle Scholar
  8. 8.
    Juma FD, Robers HJ, Trounce JR. Pharmacokinetics of cyclophosphamide and alkylating activity in man after intravenous and oral administration. Br J Clin Pharmacol 1979;8:209–17.PubMedGoogle Scholar
  9. 9.
    Slee PHThJ, De Bruijn EA, Driessen OMJ, Van Oosterom AT. Pharmacokinetics of the cytostatic drugs used in the CMF-regimen. Anticancer Res 1983;3: 269–72.PubMedGoogle Scholar
  10. 10.
    Wagner Th, Fenneberg K. Pharmacokinetics and bioavailability of cyclophosphamide from oral formulations. Arzneimittelforsch/Drug Res 1984;34(1):313–6.Google Scholar
  11. 11.
    Wagner Th, Fenneberg K. Bioavailability of cyclophosphamide from oral formulations. Eur J Clin Pharmacol 1984;26:269–70.PubMedGoogle Scholar
  12. 12.
    Matthias M, Sohr R, Preiss R, Brockmann B. Untersuchungen zur Bioverfuegbarkeit von Cyclophosphamid nach peroraler Applikation im hohen Dosisbereich. Onkologie 1984;7:48–9.PubMedGoogle Scholar
  13. 13.
    Struck RF, Alberts DS, Horne K, Phillips JG, Peng Y-M, Roe DJ. Plasma pharmacokinetics of cyclophosphamide and its cytotoxic metabolites after intravenous versus oral administration in a randomized, crossover trial. Cancer Res 1987;47:2723–6.PubMedGoogle Scholar
  14. 14.
    Bonadonna G, Valagussa P. Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 1981;304:10–5.PubMedGoogle Scholar
  15. 15.
    De Bruijn EA, Van Oosterom AT, Tjaden UR. The influence of ethanol on cyclophosphamide pharmacokinetics and metabolism in tumor-bearing rats. Pharmacol Ther 1987;33:171–7.PubMedGoogle Scholar
  16. 16.
    De Bruijn EA, Tjaden UR, Van Oosterom AT, Leeflang P, Leclerq PA. Determination of the underivatized antineoplastic drugs cyclophosphamide and 5-fluorouracil and some of their metabolites by capillary gas chromatography combined with electron-capture and nitrogen-phosphorus selective detection. J Chromatogr 1983;279:603–9.PubMedGoogle Scholar
  17. 17.
    Van den Bosch N, De Vos D. Some aspects of gas-liquid chromatographic analysis of cyclophosphamide in plasma. J Chromatogr 1980;183:49–56.PubMedGoogle Scholar
  18. 18.
    De Bruijn EA, Driessen O, Van den Bosch N, Van Strijen E. A gas-chromatographic assay for the determination of 5,6-dihydrofluorouracil and 5-fluorouracil in human plasma. J Chromatogr 1983;278:283–9.PubMedGoogle Scholar
  19. 19.
    De Bruijn EA, Van Oosterom AT, Leclercq PA, De Haan JW, Van de Ven LJM, Tjaden UR. Monitoring the behaviour of 4-ketocyclophosphamide during capillary gas chromatography by mass spectrometry. Biom Mass Spectr 1987;14:643–7.Google Scholar
  20. 20.
    Jackson AJ, Chen M-L. Application of moment analysis in assessing rates of absorption for bioequivalency studies. J Pharm Sci 1987;1:6–9.Google Scholar
  21. 21.
    Jochemsen R, Nesselman JGJ, Hermans J, Van Boxtel CJ, Breimer DD. Pharmacokinetics of brotizolam in healthy subjects following intravenous and oral administration. Br J Clin Pharmacol 1983;16:285S-290S.PubMedGoogle Scholar
  22. 22.
    Collier PS, Riegelman S. A new method for estimating absolute bioavailability from plasma level measurements of drugs. Abstracts of the 41th International Congress of Pharmaceutical Sciences of FIP, Vienna, 1981:174.Google Scholar
  23. 23.
    De Bruijn EA, Driessen O, Leeflang PA, et al. Pharmacokinetic interactions of cyclophosphamide and 5-fluorouracil with methotrexate in an animal model. Cancer Treat Rep 1986;70:1159–65.PubMedGoogle Scholar
  24. 24.
    De Bruijn EA, Driessen O, Leeflang P, Van Strijen E, Van den Bosch N, Hermans J. Interactions of methotrexate and cyclophosphamide with the pharmacokinetics of 5-fluorouracil in an animal model. Cancer Treat Rep 1987;71:1267–9.PubMedGoogle Scholar
  25. 25.
    De Bruijn EA, Driessen O, Leeflang P, Van Strijen E, Van den Bosch N, Hermans J. Interactions of methotrexate and cyclophosphamide with cyclophosphamide pharmacokinetics. Submitted for publication.Google Scholar
  26. 26.
    Van den Bosch N, Van Strijen E, Driesen O, De Bruijn EA. Non-linear pharmacokinetics of orally administered cyclophosphamide in rats and its possible influence on effects. Naunyn-Schmiedebergs Arch Pharm 1985;330:81.Google Scholar

Copyright information

© Bohn, Scheltema & Holkema 1988

Authors and Affiliations

  • E. A. De Bruijn
    • 1
  • P. H. TH. J Slee
    • 2
  • A. T. Van Oosterom
    • 1
  • D. W. Lameijer
    • 3
  • K. J. Roozendaal
    • 3
  • U. R. Tjaden
    • 4
  1. 1.Laboratory of Cancer Research & Clinical OncologyUniversity of AntwerpWilrijkBelgium
  2. 2.St. Antonius ZiekenhuisEM Nieuwegeinthe Netherlands
  3. 3.Onze Lieve Vrouwe GasthuisHA Amsterdamthe Netherlands
  4. 4.Center for Bio-Pharmaceutical SciencesRA Leidenthe Netherlands

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