Cancer Chemotherapy and Pharmacology

, Volume 27, Issue 2, pp 157–160 | Cite as

Alteration of dacarbazine pharmacokinetics after interleukin-2 administration in melanoma patients

  • Guy G. Chabot
  • Lawrence E. Flaherty
  • Manuel Valdivieso
  • Laurence H. Baker
Original Articles Decarbazine Pharmacokinetics, Interleukin-2, Melanoma


In an effort to improve the treatment of metastatic malignant melanoma, we evaluated the sequential administration of the chemotherapeutic agent dacarbazine (DTIC) and the biological response modifier interleukin-2 (rIL-2) in a phase I–II study. Since the combination of biological response modifiers and chemotherapeutic agents could alter drug disposition, we evaluated the pharmacokinetics of DTIC and its major metabolite, 5-aminoimidazole 4-carboxamide (AIC), before and after rIL-2 administration. DTIC (1 g/m2, 24-h i.v. infusion) was given on day 1 and rIL-2 (2–4 million Cetus units/m2, 30-min i.v. injection), on days 15–19 and 22–26 of each course of therapy. The second DTIC dose was given on day 29, i.e., 3 days after the last rIL-2 administration. DTIC and AIC were assayed by reversed-phase HPLC. DTIC plasma levels showed a significant decrease after rIL-2 administration as compared with DTIC values obtained in the same patients before rIL-2 administration. DTIC area under the curve (AUC) values obtained after rIL-2 were lower than those obtained on day 1 before rIL-2 administration (P=0.02). After rIL-2, the total body clearance (ClT) was increased (P=0.04), as was the volume of distribution at steady state (Vss;P=0.02). The decrease in AUC after rIL-2 administration became more pronounced as the rIL-2 dose was increased (P=0.03). No significant difference was detected in the elimination phase of DTIC when halflives obtained before and after rIL-2 administration were compared; the mean half-lives were 0.7 and 2.8 h for the α- and β-phases, respectively. The model-independent mean residence time was 3.4 h. The plasma AUC for the metabolite AIC did not charge after rIL-2 administration. AIC biphasic plasma elimination was also similar after rIL-2 administration, with α- and β-half-lives of 0.7 and 11.4 h, respectively. Urinary excretion of DTIC and AIC did not differ after rIL-2 administration; the overall DTIC excretion was 39% of the dose over 48 h, and AIC urinary excretion was 25% of the DTIC dose. The observed decrease in the DTIC plasma AUC after rIL-2 administration appears to be due to an increase in the volume of distribution, since other factors such as half-lives, urinary excretion, and metabolism were not significantly altered. The clinical consequences of the rIL-2-DTIC interaction remain difficult to assess based on presently available data, but this drug interaction should be taken into consideration in the development of future chemo-immunotherapy regimens that include high-dose rIL-2.


Melanoma Urinary Excretion Metastatic Malignant Melanoma Melanoma Patient Drug Disposition 
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Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • Guy G. Chabot
    • 1
  • Lawrence E. Flaherty
    • 1
  • Manuel Valdivieso
    • 1
  • Laurence H. Baker
    • 1
  1. 1.Division of Hematology and OncologyWayne State University of MedicineDetroitUSA

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