Metabolic fate of amrinone. 1. Distribution and excretion after intravenous administration of carbon 14 labelled amrinone in rats and dogs


Esumi, Y.; Nanbo, T.; Otsuki, T.; Ninomiya S I.; Yokota, T.; Kobayashi S I.

Oyo Yakuri 38(2): 131-144

1989


The distribution and excretion of radioactivity were studied in rats and dogs after intravenous administration of 14C-labeled amrinone at a dose of 5 or 50 mg/kg. 1. In male rats given the 5 mg/kg dose, a maximum blood concentration of 4.72 .mu.g equiv. of amrinone/ml was found after 5 min. Radioactivity in blood was eliminated in a biphasic manner. The initial half-life was 1.1 hr, ranging from 5 min to 6 hr, and the terminal half-life was 65 hr, ranging from 24 to 72 hr. The initial elimination up to 1 hr was less in percentage after the 50 mg/kg dose than after the 5 mg/kg dose; however, the terminal elimination wa snot markedly different in percentage after the two different doses. The area under the time versus blood concentration curve (AUC) after the 50 mg/kg dose was 22 times as large as the AUC after the 5 mg/kg dose. 2. In male dogs given the 5 mg/kg dose, a maximum blood concentration of 5.99 .mu.g equiv. of amrinone/ml was found after 5 min. Initial and terminal half-lives were 2.1 hr (5 min-8 hr) and 58 hr (24-72 hr), respectively. 3. Within 120 hr after the 5 mg/kg dose, male rats excreted 85.7% of the dose in the urine and 12.9% in the feces. Bile-duct cannulated male rats excreted 27.1% of the dose in the bile, 65.7% in the urine and 4.4% in the feces within 48 hr after dosing. When the first 24 hr bile obtained from male rats having been given 14C-labeled amrinone was introduced into the duodenum of different male rats, the recipient rats excreted 20.9% of the administered radioactivity in the urine and 12.2% in the bile. 4. Within 120 hr after the 5 mg/kg dose, male dogs excreted 67.9% of the dose in the urine and 26.4% in the feces. Bile-duct cannulated male dogs excreted 19.9% of the dose in the bile, 69.7% in the urine and 1.0% in the feces within 48 hr after dosing. 5. In male rats given the 5 mg/kg dose, maximum tissue concentrations were found after 5 min in the tissues examined except in the testis. The concentrations in the kidney, liver, aorta and stomach were high and the concentrations in the central nervous system, fat and testis were low. The whole-body autoradiograms of rats killed 5 min after dosing showed that radioactivity was highly distributed in the renal medulla after the 5 mg/kg dose and in the renal cortex after the 50 mg/kg dose and that radioactivity was dotted in the lung more markedly after the 50 mg/kg dose than after the 5 mg/kg dose but it disappeared rapidly. 6. When female rats were given the 5 mg/kg dose on day 13 or 19 of pregnancy, the concentrations of radioactivity in the fetuses were low, that is, 18% and 15%, respectively, of the concentration in the maternal plasma. 7. When lactating rats were given the 5 mg/kg dose, the concentration of radioactivity in the milk was 7-16 times as high as the concentration in the maternal blood up to 12 hr after dosing.