Effect of dexrazoxane on doxorubicin pharmacokinetics in young and old rats.
OBJECTIVE
Although dexrazoxane (ICRF-187) is used clinically to protect against doxorubicin cardiotoxicity, the age-related effect of dexrazoxane on doxorubicin pharmacokinetics has not been well studied.


METHODS
We therefore examined the effect of pretreatment with dexrazoxane (50 mg kg(-1) i.p. 1 h prior to administration of doxorubicin 2 mg kg(-1) i.v. bolus) on doxorubicin and doxorubicinol pharmacokinetics in Fischer 344 rats at 5 months of age (young adult) and 22 months of age (old).


RESULTS
Dexrazoxane had no major effects on doxorubicin or doxorubicinol pharmacokinetics in plasma or heart in either young or old rats. However, age had significant effects on anthracycline pharmacokinetics. Early plasma concentrations were increased and systemic clearance of doxorubicin was decreased in old compared with young rats. Cardiac concentrations of doxorubicin (AUC) were significantly increased in old rats. In addition cardiac doxorubicinol concentrations (AUC 0-72 h) were increased by over 80% in old compared to young rats.


CONCLUSIONS
The results suggest that dexrazoxane does not alter doxorubicin pharmacokinetics. In contrast, aging in the rat model is associated with altered doxorubicin and doxorubicinol pharmacokinetics, in particular in the heart. These changes could increase the risk of anthracycline cardiotoxicity with age.
Cusack
Barry J
BJ
VA Medical Center, 500 West Fort Street, Boise, ID 82702-4598, USA. barry.cusack@med.va.gov
Musser
Beth
B
Gambliel
Hervé
H
Hadjokas
Nicholas E
NE
Olson
Richard D
RD
D000367:Age Factors; D000375:Aging; D000818:Animals; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011929:Razoxane / Q000494:pharmacology*
D011929:Razoxane; D004317:Doxorubicin; C010013:adriamycinol