Cancer Chemotherapy and Pharmacology

, Volume 35, Issue 1, pp 59–63 | Cite as

Cyclophosphamide, cisplatin, and carmustine: pharmacokinetics of carmustine following multiple alkylating-agent interactions

  • Roy B. Jones
  • Steven Matthes
  • Douglas Kemme
  • Christopher Dufton
  • Sophie Kernan
Original Article Carmustine, Pharmacokinetics, Alkylating Agents


Cyclophosphamide, cisplatin, and carmustine (CPA/cDDP/BCNU) constitute a combination alkylating-agent regimen commonly used with autologous marrow support. Its therapeutic effectiveness is accompanied by sporadic life-threatening and fatal toxicities, the most common of which is acute lung injury. We have previously shown that variation in the BCNU AUC can be correlated to the risk of pulmonary injury in patients receiving CPA/cDDP/BCNU. In an attempt to understand further the role of interpatient variation in drug pharmacokinetics (PK) with respect to pharmacodynamic outcomes, we evaluated the effect of pretreatment with CPA, cDDP, or both on BCNU PK in male Sprague-Dawley rats. The drug-administration pattern was designed to mimic that of the CPA/cDDP/BCNU regimen in patients. Each pretreatment increased both the absolute value of and the variation in BCNU AUC relative to the control values. These findings are consistent with an important rate-limiting elimination pathway for BCNU in rats and may explain the wide interpatient variability of BCNU AUC and the sporadic pulmonary toxicity seen in patients receiving CPA/cDDP/BCNU.

Key words

Carmustine Pharmacokinetics Alkylating agents 


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  1. 1.
    Armitage JO, Antman KH (1992) High-dose cancer therapy. Pharmacology, hematopoietins, stem cells. Williams and Wilkins, BaltimoreGoogle Scholar
  2. 2.
    Peters WP, Eder JP, Henner WD, Bast RC Jr, Schnipper L, Frei E III (1985) Novel toxicities associated with high-dose combination alkylating agents and autologous bone marrow support. In: Dicke KA, Spitzer G, Zander AR (eds) Autologous bone marrow transplantation. Proceedings of the first international symposium. University of Texas M. D. Anderson Hospital and Tumor Institute, Houston, TexasGoogle Scholar
  3. 3.
    Skipper HE (1979) Combination therapy: some concepts and results. Cancer Res 17:215–257Google Scholar
  4. 4.
    Cancer and Leukemia Group B (1990) Protocol 9082, Southwest Oncology Group trial 9114, a randomized comparative study of high dose cyclophosphamide, cisplatin, and BCNU (CPA/cDDP/BCNU) and autologous bone marrow support versus standard dose CPA/cDDP/BCNU as consolidation to adjuvant CAF for patients with operable stage II or stage III breast cancer involving >10 axillary lymph nodes, phase III. NCIGoogle Scholar
  5. 5.
    Collins JM, Zaharko DS, Dedrick RL, Chabner BA (1986) Potential roles for preclinical pharmacology in phase I clinical trials. Cancer Treat Rep 70:73–80Google Scholar
  6. 6.
    Cohen MH, Johnston-Early A, Hood MA, et al. (1985) Drug precipitation within i. v. tubing: a potential hazard of chemotherapy administration. Cancer Treat Rep 69:1325–1326Google Scholar
  7. 7.
    Jones RB, Matthes S, Shpall EJ, Stemmer S, Bearman SI (1993) Acute lung injury following treatment with high-dose cyclophosphamide, cisplatin, and carmustine: pharmacodynamic evaluation of carmustine. J Natl Cancer Inst 85:640–647Google Scholar
  8. 8.
    Bartlett MS (1937) Some examples of statistical research in agriculture and applied biology. J R Stat Soc 4:137–170Google Scholar
  9. 9.
    Cox DR, Oakes D (1984) Analysis of survival data. Chapman and Hall 1984, NYGoogle Scholar
  10. 10.
    Henner WD, Peters WP, Eder JP, et al. (1986) Pharmacokinetics and immediate effects of high-dose carmustine in man. Cancer Treat Rep 70:877–883Google Scholar
  11. 11.
    Phillips GL, Fay JW, Herzig GP, et al. (1983) A phase I–II study; intensive BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea, NSC 409 962) and autologous bone marrow transplantation for refractory cancer. Cancer 52:1792–1802Google Scholar
  12. 12.
    Peters WP, Eder JP, Henner WS, Schryber S, Wilmore D, Finberg R, Shoenfeld D, Bast R, Gargone B, Antman K, Anderson K, Kruskall MS, Schnipper L, Frei E (1986) High dose combination alkylating agents with autologous bone marrow support: a phase I trial. J Clin Oncol 4:646–654Google Scholar
  13. 13.
    Aronin PA, Mahaley MS, Rudnick SA, Dudka L, Donohue JF, Selker RG (1980) Prediction of BCNU pulmonary toxicity in patients with malignant gliomas. An assessment of risk factors. N Engl J Med 303:183–188Google Scholar
  14. 14.
    Jones RB, Matthes S, Dufton C, Bearman SI, Stemmer SM, Myers S, Shpall EJ (1993) Pharmacokinetic/pharmacodynamic interactions of intensive cyclophosphamide, cisplatin, and BCNU in patients with breast cancer. Breast Cancer Res Treat 26:S11-S17Google Scholar
  15. 15.
    Chattergi UC, Greene RF, Gallelli JF (1978) Mechanism of hydrolysis of halogenated nitrosoureas. J Pharm Sci 67:1527–1532Google Scholar
  16. 16.
    Colvin M, Brundrett RB, Cowens JW, et al (1976) A chemical basis for the antitumor activity of chloroethylnitrosoureas. Biochem Pharmacol 25:695Google Scholar
  17. 17.
    Levin VA, Stearns J, Byrd A, et al (1979) The effect of phenobarbital pretreatment on the antitumor activity of 1,2-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and 1-(2-chloroethyl)-3-(2,6-dioxo)-3-piperidyl-1-nitrosourea on the plasma pharmacokinetics and biotransformation of BCNU. J Pharmacol Exp Ther 208:1Google Scholar
  18. 18.
    Hill DL, Kirk MC, Struck RF (1975) Microsomal metabolism of nitrosoureas. Cancer Res 35:296Google Scholar
  19. 19.
    Potter DW, Reed DJ (1983) Involvement of FMN and phenobarbital cytochrome P-450 in stimulating a one-electron reductive denitrosation of 1-(2-chloroethyl)-3-(cyclohexyl)-1-nitrosourea catalyzed by NADPH-cytochrome P-450 reductase. J Biol Chem 258:6906–6911Google Scholar
  20. 20.
    Hill DL (1976)N,N′-Bis(2-chloroethyl)-N-nitrosourea (BCNU), a substrate for glutathione (GSH) S-transferase (abstract). Proc Am Soc Clin Res 17:52Google Scholar
  21. 21.
    Smith MT, Evans CG, Doane-Selzer P, Castro VM, Tahir MK, Mannervik B (1989) Denitrosation of 1,3-bis(2-chloroethyl)-1-nitrosourea by class mu glutathione transferases and its role in cellular resistance in rat brain tumor cells. Cancer Res 49:5954–5958Google Scholar
  22. 22.
    Talcott RE, Levin VA (1983) Glutathione-dependent denitrosation ofN,N′-bis(2-chloroethyl)-N-nitrosourea (BCNU): nitrite release catalyzed by mouse liver cytosol in vitro. Drug Metab Dispos 11:175–176Google Scholar
  23. 23.
    DeVita VT, Denham C, Davidson JD, et al (1967) The physiological disposition of the carcinostatic 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) in man and animals. Clin Pharmacol Ther 8:566–577Google Scholar
  24. 24.
    LeBlanc GA, Sundseth SS, Weber GF, Waxman DJ (1992) Platinum anticancer drugs modulate P-450 mRNA levels and differentially alter hepatic drug and steroid hormone metabolism in male and female rats. Cancer Res 52:540–547Google Scholar
  25. 25.
    Andrews PA, Schiefer MA, Murphy MP, et al (1988) Enhanced potentiation of cisplatin cytotoxicity in human ovarian carcinoma cells by prolonged glutathione depletion. Chem Biol Interact 65:51–58Google Scholar
  26. 26.
    Gurtoo HL, Marinello AJ, Berrigan MJ, Bansal SK, Paul B, Pavelic ZP, Struck RF (1983) Effect of thiols on toxicity and carcinostatic activity of cyclophosphamide. Semin Oncol 10:35–45Google Scholar
  27. 27.
    LeBlanc GA, Waxman DJ (1990) Mechanisms of cyclophosphamide action on hepatic P-450 expression. Cancer Res 50:5720–5726Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Roy B. Jones
    • 1
  • Steven Matthes
    • 1
  • Douglas Kemme
    • 1
  • Christopher Dufton
    • 1
  • Sophie Kernan
    • 1
  1. 1.Bone Marrow Transplant ProgramUniversity of Colorado Cancer CenterDenverUSA

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