Summary
We compared the pharmacokinetics of daunomycin in two groups of rats: one group was treated with daunomycin (7.5 mg/kg) alone and the other group was treated with daunomycin (7.5 mg/kg) plus the calcium antagonist verapamil (2x50 mg/kg i. p.). Due to a much slower decrease in plasma concentrations the daunomycin AUCO→∞ was dramatically increased (8 times) in the animals treated with anthracycline plus verapamil. The daunomycin plasma clearance was found to be decreased about 9 times in the verapamil-treated group. Verapamil had a differential effect on the tissue distribution of daunomycin. Of the organs examined the heart, liver, and lungs showed an increased (about 2–3 times) AUC of daunomycin. In the kidneys and spleen the AUCs of daunomycin were about equal in both groups of rats, while in the femoral bone marrow the daunomycin AUC was significantly reduced by the simultaneous administration of verapamil. Our data suggest that an increased risk for anthracycline-induced cardiotoxicity can be anticipated by the combined treatment of anthracycline drugs with calcium antagonists.
References
Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE (1966) Quantitative comparison of toxicity of anticancer agents in mouse, rat, dog, monkey and man. Cancer Chemother Rep 50:219
Kerr DJ, Graham J, Cummings J, Morrison JG, Thompson GG, Brodie MJ, Kaye SB (1986) The effect of verapamil on the pharmacolinetics of adriamycin. Cancer Chemother Pharmacol 18:239
Legha SS, Benjamin RS, Mackay B, Ewer M, Wallace S, Valdivieso M, Rasmussen S, Blumenschein GR, Freireich EJ (1982) Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 96:133
Nooter K, Sonneveld P, Martens A (1985) Differences in the pharmacokinetics of daunomycin in normal and leukemic rats. Cancer Res 45:4020
Ozols RF, Rogan AM, Hamilton TC, Klecker R, Young RC (1984) Verapamil (V) plus adriamycin (ADR) in refractory ovarian cancer (OC): design of a clinical trial on basis of reversal of ADR resistance (R) in human OC cell lines (CL). Proc Am Assoc Cancer Res 25:300
Presant CA, Kennedy P, Wiseman C, Gala K, Wyres M (1984) Verapamil (V) plus adriamycin (A)—phase I-II clinical study. Proc Am Soc Clin Oncol 2:32
Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1982) Increased accumulation of vincristine and adriamycin in drug-resistant tumor cells following incubation, with calcium antagonists and calmodulin inhibitors. Cancer Res 42:4730
Wagner J (1975) Fundamentals of clinical pharmacokinetics, Hamilton Press, Hamilton, Alabama, pp 237–330
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Nooter, K., Oostrum, R. & Deurloo, J. Effects of verapamil on the pharmacokinetics of daunomycin in the rat. Cancer Chemother. Pharmacol. 20, 176–178 (1987). https://doi.org/10.1007/BF00253975
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DOI: https://doi.org/10.1007/BF00253975