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Plasma concentration, distribution and excretion of radioactivity were investigated after a single and repeated intravenous administration of 5 mg/kg of 14C-milrinone to male rats. 1. After a single dosing, the plasma concentrations declined bi-phasically with the elimination half life (t1/2) of 3.5 hr; the area under the plasma concentration-time curve (AUC), volume of distribution (Vdss) and total clearance (CLtotal) were 7.19 μg equiv. of milrinone·hr/ml, 873 ml/kg and 11.6 ml/min/kg, respectively. Plasma concentration-time curve of unchaged drug was similar to that of radioactivity. The AUC, t1/2, Vdss and CLtotal for unchaged drug were 3.2 hr, 7.35 μg·hr/ml, 727 ml/kg and 11.3 ml/min/kg, respectively. 2. Radioactivity was distributed rapidly to various tissues, showing peak levels 15 min after a single administration. At 15 min, levels of radioactivity in the kidney was approximately 4 times higer than that in the plasma, while concentrations in other tissues were similar to or lower than plasma concentrations. Radioactivity disappeared rapidly from most tissues, except the skin. After repeated administration of 14C-milrinone for 7 days, no radioactivity was accumulated in any tissues measured however, disappearance from the skin was relative ly slow. On the whole body autoradiogram 24 hr after repeated dosing, revealed that radioactivity was not observed in skin but was seen in the hair. At 72 hr, radioactivity was detected in the hair only, but the level was low. 3. Within 168 hr after a single dosing, 79.2% and 21.9% of dosed radioactivity were excreted in urine and feces, respectively, and 101.1% of the dose was recovered by both routes. After repeated dosing with 14C-milrinone for 7 days, cumulative excretion rates of radioactivity in urine and feces were 74.9% and 21.4%, being similar to those after a single dosing. Within 48 hr after administration of 14C-milrinone to bile duct-cannulated rats, 65.1%, 10.4% and 18.9% of dosed radioactivity were excreted in the urine, feces and bile, respectively, indicating that renal excretion was the main excretion route of milrinone.

Plasma Concentration, Distribution and Excretion of 14C-Milrinone in Rats following Single and Repeated Intravenous Administration.