Metabolism of dexrazoxane (ICRF-187) used as a rescue agent in cancer patients treated with high-dose etoposide
Research output: Contribution to journal › Journal article › Research › peer-review
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 micro M 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 micro M 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.
Original language | English |
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Book series | Cancer Chemotherapy and Pharmacology |
Volume | 52 |
Issue number | 2 |
Pages (from-to) | 167-74 |
Number of pages | 8 |
ISSN | 0344-5704 |
DOIs | |
Publication status | Published - Aug 2003 |
- Aged, Antineoplastic Agents, Phytogenic/therapeutic use, Brain Neoplasms/drug therapy, Carcinoma, Non-Small-Cell Lung/drug therapy, Chemotherapy, Adjuvant, Ethylenediamines/blood, Etoposide/administration & dosage, Female, Glycine/analogs & derivatives, Half-Life, Humans, Infusions, Intravenous, Lung Neoplasms/drug therapy, Male, Middle Aged, Razoxane/administration & dosage
Research areas
ID: 247891888