Effects of verapamil on the pharmacokinetics of daunomycin in the rat.

We compared the pharmacokinetics of daunomycin in two groups of rats: one group was treated with daunomycin (7.5 mg/kg) alone and the other group was treated with daunomycin (7.5 mg/kg) plus the calcium antagonist verapamil (2 X 50 mg/kg i.p.). Due to a much slower decrease in plasma concentrations the daunomycin AUC0----infinity was dramatically increased (8 times) in the animals treated with anthracycline plus verapamil. The daunomycin plasma clearance was found to be decreased about 9 times in the verapamil-treated group. Verapamil had a differential effect on the tissue distribution of daunomycin. Of the organs examined the heart, liver, and lungs showed an increased (about 2-3 times) AUC of daunomycin. In the kidneys and spleen the AUCs of daunomycin were about equal in both groups of rats, while in the femoral bone marrow the daunomycin AUC was significantly reduced by the simultaneous administration of verapamil. Our data suggest that an increased risk for anthracycline-induced cardiotoxicity can be anticipated by the combined treatment of anthracycline drugs with calcium antagonists.