Metabolism of dexrazoxane (ICRF-187) used as a rescue agent in cancer patients treated with high-dose etoposide
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Metabolism of dexrazoxane (ICRF-187) used as a rescue agent in cancer patients treated with high-dose etoposide. / Schroeder, Patricia E; Jensen, Peter Buhl; Sehested, Maxwell; Hofland, Kenneth Francis; Langer, Seppo W; Hasinoff, Brian B.
In: Cancer Chemotherapy and Pharmacology, Vol. 52, No. 2, 08.2003, p. 167-74.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Metabolism of dexrazoxane (ICRF-187) used as a rescue agent in cancer patients treated with high-dose etoposide
AU - Schroeder, Patricia E
AU - Jensen, Peter Buhl
AU - Sehested, Maxwell
AU - Hofland, Kenneth Francis
AU - Langer, Seppo W
AU - Hasinoff, Brian B
PY - 2003/8
Y1 - 2003/8
N2 - 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.
AB - 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.
KW - Aged
KW - Antineoplastic Agents, Phytogenic/therapeutic use
KW - Brain Neoplasms/drug therapy
KW - Carcinoma, Non-Small-Cell Lung/drug therapy
KW - Chemotherapy, Adjuvant
KW - Ethylenediamines/blood
KW - Etoposide/administration & dosage
KW - Female
KW - Glycine/analogs & derivatives
KW - Half-Life
KW - Humans
KW - Infusions, Intravenous
KW - Lung Neoplasms/drug therapy
KW - Male
KW - Middle Aged
KW - Razoxane/administration & dosage
U2 - 10.1007/s00280-003-0619-7
DO - 10.1007/s00280-003-0619-7
M3 - Journal article
C2 - 12750840
VL - 52
SP - 167
EP - 174
JO - Cancer Chemotherapy and Pharmacology, Supplement
JF - Cancer Chemotherapy and Pharmacology, Supplement
SN - 0943-9404
IS - 2
ER -
ID: 247891888