Metabolism of dexrazoxane (ICRF-187) used as a rescue agent in cancer patients treated with high-dose etoposide.
OBJECTIVE
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.
Schroeder
Patricia E
PE
Faculty of Pharmacy, University of Manitoba, 50 Sifton Road, R3T 2N2, Winnipeg, Manitoba, Canada.
Jensen
Peter Buhl
PB
Sehested
Maxwell
M
Hofland
Kenneth Francis
KF
Langer
Seppo W
SW
Hasinoff
Brian B
BB
D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000556:secondary; D017024:Chemotherapy, Adjuvant; D005029:Ethylenediamines / Q000097:blood; D005047:Etoposide / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011929:Razoxane / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D005029:Ethylenediamines; D011929:Razoxane; D005047:Etoposide; C059866:ICRF 198; D005998:Glycine