VERAPAMIL-REVERSING CONCENTRATIONS INDUCE BLOOD-FLOW CHANGES THAT COULD COUNTERACT IN-VIVO THE MDR-1-MODULATING EFFECTS

Background. Intraarterial hepatic (IAH) administration of verapamil sh ould achieve mdr-1-reversing concentrations with reduced cardiac toxic ity. The authors have explored the tolerance of its IAH administration and its effects on doxorubicin pharmacodynamics. Methods. Verapamil w as given to rabbits by intravenous or IAH administration, and its effe cts on heart rates were compared. Doxorubicin then was given intraveno usly either with IAH verapamil or with an IAH control perfusion, and t umor and liver drug concentrations were determined. Hepatic blood flow changes were studied by the administration of Tc-99m-albumin macroagg regates (Tc-99m-MAA) under verapamil IAH perfusions. Results. Compared with the intravenous route, IAH administration of verapamil was not t oxic, and cardiac effects were reduced significantly. Its effect on do xorubicin distribution was detrimental, because the tumor-liver doxoru bicin concentration ratios were lower in the verapamil group (0.23 vs. 3.37; P < 0.05). Tumor doxorubicin concentrations were lower when ver apamil was coinfused (43 vs. 573 ng/100 mg tissue; P < 0.05). In norma l liver tissue, increased amounts of doxorubicin and metabolites were observed. The verapamil IAH perfusions with Tc-99m-MAA confirmed a dif ferential action on tumor and normal vessels; the distribution of radi onuclide was diverted away from the tumor bed significantly when verap amil was administered (tumor-to-liver ratio of 25.3 control rabbits vs . 5.99 rabbits who received verapamil; P < 0.05). Conclusions. Reversi ng the concentrations of verapamil provoked changes in the distributio n of the liver blood flow. The hemodynamic effects of verapamil region al perfusions could counteract in vivo its potential mdr-1-reversing p roperties.