Effects of verapamil on the acute toxicity of doxorubicin in vivo.

BACKGROUND

Studies indicating that verapamil substantially enhances doxorubicin levels in certain drug-resistant tumor cells have led to the use of verapamil in combination with doxorubicin in animal and clinical studies of multidrug-resistant tumors. These studies have shown this drug combination to be associated with severe toxic effects. It is important to determine whether verapamil modulates the dose-limiting and potentially lethal cardiotoxicity of doxorubicin and to elucidate possible mechanisms.

PURPOSE

The aims of this study were to evaluate the in vivo effects of verapamil on (a) doxorubicin-stimulated cardiac lipid peroxidation and cardiac damage, (b) doxorubicin-induced animal mortality, and (c) biodistribution of doxorubicin to the heart.

METHODS

Male (BALB/c x DBA/2)F1 mice were treated with a high dose of doxorubicin (15 mg/kg, injected intraperitoneally), verapamil (25 mg/kg, injected intraperitoneally), or combinations of the two. Lipid peroxidation was determined using the 2-thiobarbituric acid assay for malonaldehyde. Light microscopy was used for histopathologic examination of cardiac tissue. A fluorometric assay procedure was employed to determine doxorubicin levels in the heart.

RESULTS

Verapamil was an effective inhibitor of peroxidative damage to myocardial lipids following a high dose of doxorubicin (15 mg/kg, injected intraperitoneally). However, mice treated with verapamil and doxorubicin had a lower survival rate and a higher initial peak concentration of doxorubicin in the heart than those treated with doxorubicin alone. They also demonstrated a higher incidence and severity of degenerative changes in cardiac tissue.

CONCLUSIONS

Our findings suggest that verapamil effectively inhibits doxorubicin-mediated lipid peroxidation in vivo but that cardiac lipid peroxidation is not the major limiting mechanism underlying doxorubicin-induced toxicity. A possible explanation for the excess mortality and cardiac injury in mice treated with verapamil plus doxorubicin is that verapamil alters the pharmacokinetics of doxorubicin.

IMPLICATIONS

Further studies are necessary for development of safer protocols and/or drug combinations to treat multidrug-resistant tumors. We are currently studying treatment of tumor-bearing animals with a cumulative dosage regimen of doxorubicin in the presence and absence of verapamil.