Correlation between the disposition of [14C]clofilium and its cardiac electrophysiological effect

The disposition of [14C]clofilium was studied in rats and dogs and related to the electrophysiological effects observed in isolated canine Purkinje fibers. Ten percent of the dose of [14C] clofilium administered to rats and dogs i.v. was excreted in the urine within 72 hr, whereas 55% was excreted in the feces during the same period in both species. In rats, biliary excretion accounted for 35% of the dose within 48 hr. Plasma levels of radioactivity rapidly decline in rats and dogs administered 5 mg/kg of [14C]clofilium characterized by a plasma radioactivity half-life for the elimination phase of 2.5 to 3 hr. In contrast, tissue levels of radioactivity were persistent; the half-life of radioactivity in the rat heart was 5 days and 14 days in the dog heart. Twenty-four hours after an i.v. dose of clofilium (0.044-1.3 mg/kg) to dogs, the action potential duration of isolated Purkinje fibers was prolonged in a dose-dependent manner. The half-life of the effect of clofilium on action potential duration as 10 days which is in agreement with the persistence of radioactivity in tissues. The data suggest that [14C]clofilium and/or metabolites concentrate in the heart and that plasma levels of radioactivity may not be an accurate index of cardiac levels or biological response.