Effect of dexrazoxane on doxorubicin pharmacokinetics in young and old rats.

PURPOSE: 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. CONCLUSION: 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.

Arginine to lysine 108 substitution in recombinant CYP1A2 abolishes methoxyresorufin metabolism in lymphoblastoid cells.

1. Cytochrome P4501A2 (CYP1A2) activates a large number of procarcinogens to carcinogens. Phytochemicals such as flavones can inhibit CYP1A2 activity competitively, and hydroxylated derivatives of flavone (galangin) may be potent, selective inhibitors of CYP1A2 activity relative to CYP1A1 activity. Molecular modelling of the CYP1A2 interaction with hydroxylated derivatives of flavone suggests that a number of hydrophobic residues of the substrate-binding domain engage in hydrogen bonding with such inhibitors. 2. We have tested this model using site-directed mutagenesis of these residues in expression plasmids transfected into the human B-lymphoblastoid cell line, AHH-1 TK+/-. 3. Consistent with the molecular model's predicted placement in the active site, amino acid substitutions at the predicted residues abolished CYP1A2 enzymatic activity. 4. Transfected cell lines contained equal amounts of immunoreactive CYP1A2. 5. Our results support the molecular model's prediction of the critical amino acid residues present in the hydrophobic active site, residues that can hydrogen bond with CYP1A2 inhibitors and modify substrate binding and/or turnover.