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

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 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.

• Authors: Patricia E Schroeder, Peter Buhl Jensen, Maxwell Sehested, Kenneth Francis Hofland, Seppo W Langer, Brian B Hasinoff
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 52 Issue 2 Pg. 167-74 (Aug 2003) ISSN: 0344-5704 [Print] Germany
• PMID: 12750840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Ethylenediamines
• Razoxane
• Etoposide
• ICRF 198
• Glycine

Topics

• Aged
• Antineoplastic Agents, Phytogenic (therapeutic use)
• Brain Neoplasms (drug therapy, secondary)
• Carcinoma, Non-Small-Cell Lung (drug therapy, secondary)
• Chemotherapy, Adjuvant
• Ethylenediamines (blood)
• Etoposide (administration & dosage, therapeutic use)
• Female
• Glycine (analogs & derivatives, blood)
• Half-Life
• Humans
• Infusions, Intravenous
• Lung Neoplasms (drug therapy, pathology)
• Male
• Middle Aged
• Razoxane (administration & dosage, blood, metabolism)