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Metabolism of dexrazoxane (ICRF-187) used as a rescue agent in cancer patients treated with high-dose etoposide

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Abstract

Purpose

The study was undertaken to determine the metabolism of dexrazoxane (ICRF-187) to its one-ring open hydrolysis products and its two-rings opened metal-chelating product ADR-925 in cancer patients with brain metastases treated with high-dose etoposide. In this phase I/II trial dexrazoxane was used as a rescue agent to reduce the extracerebral toxicity of etoposide.

Methods

Dexrazoxane and its one-ring open hydrolysis products were determined by HPLC and ADR-925 was determined by a fluorescence flow injection assay.

Results

The two one-ring open hydrolysis intermediates of dexrazoxane appeared in the plasma at low levels upon completion of dexrazoxane infusion and then rapidly decreased with half-lives of 0.6 and 2.5 h. A plasma concentration of 10 μM ADR-925 was also detected at the completion of the dexrazoxane i.v. infusion period, indicating that dexrazoxane was rapidly metabolized in vivo. A plateau level of 30 μM ADR-925 was maintained for 4 h and then slowly decreased. The pharmacokinetics of dexrazoxane were found to be similar to other reported data in other settings and at lower doses.

Conclusions

The rapid appearance of ADR-925 in plasma may make ADR-925 available to be taken up by heart tissue and bind free iron. These results suggest that the dexrazoxane intermediates are enzymatically metabolized to ADR-925 and provide a pharmacodynamic basis for the antioxidant cardioprotective activity of dexrazoxane.

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Abbreviations

AUC0→∞ :

Area under the curve from time zero to infinity

Cmax :

Concentration of drug at time zero

Cltot :

Total clearance

DHOase:

Dihydroorotase

DHPase:

Dihydropyrimidine amidohydrolase or dihydropyrimidinase

HPLC:

High-pressure liquid chromatography

Kf :

Equilibrium formation constant

Poct :

Octanol-water partition coefficient

t1/2 :

Half-time

tr :

Retention time

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Acknowledgements

This work was supported by the Canadian Institutes of Health Research, the Canada Research Chairs program, and a Canada Research Chair in Drug Development for B.H. and grant support for K.H. by a H:S Research Council (Denmark). P.S. was supported by a Manitoba Health Research Council studentship and a Canadian Institutes of Health Research studentship.

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Authors and Affiliations

  1. Faculty of Pharmacy, University of Manitoba, 50 Sifton Road, Winnipeg, Manitoba, R3T 2N2, Canada

    Patricia E. Schroeder & Brian B. Hasinoff

  2. Laboratory of Experimental Medical Oncology, The Laboratory Center, The National University Hospital, DK-2100, Copenhagen, Denmark

    Peter Buhl Jensen, Kenneth Francis Hofland & Seppo W. Langer

  3. The Finsen Center and Department of Pathology, The National University Hospital, DK-2100, Copenhagen, Denmark

    Maxwell Sehested

Authors
  1. Patricia E. Schroeder
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  2. Peter Buhl Jensen
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  3. Maxwell Sehested
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  4. Kenneth Francis Hofland
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  5. Seppo W. Langer
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  6. Brian B. Hasinoff
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Correspondence to Brian B. Hasinoff.

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Schroeder, P.E., Jensen, P.B., Sehested, M. et al. Metabolism of dexrazoxane (ICRF-187) used as a rescue agent in cancer patients treated with high-dose etoposide. Cancer Chemother Pharmacol 52, 167–174 (2003). https://doi.org/10.1007/s00280-003-0619-7

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