DISPOSITION AND METABOLISM OF [C-14] AMEZINIUM METILSULFATE IN RATS

Disposition and metabolism of [14C]-amezinium metilsulfate (4-amino-6-methoxy-1-phenylpyridazinium methylsulfate, Risumic) were systematically studied in rats after intravenous (5 mg/kg) or oral (20, 100 mg/kg) administration. After oral administration at 20 mg/kg, blood level reached the maximum (Cmax) of 0.65 .mu.g eq/ml at 3 h (tmax) and decreased with t11/2 of 8.1 h. Levels in plasma and most tissues elevated to the Cmax at 3 h. The liver level was the highest (61 times as high as plasma level of all examined tissues. Most tissues levels decreased thereafter essentially in parallel with plasma levels. The finding by whole-body autoradiography essentially agreed with those by radiometry. In lactating rats, milk levels were virtually similar to plasma levels. [14C]-Amezinium metilsulfate radioactivity in fetus and fetal blood was around 0.3 .mu.g/g, being about 1/10 level of maternal plasma level. About 24, 72 and 42% were excreted in urine, feces and bile, respectively. Re-absorption of biliary metabolite accouted for about 31%, being about 13% or orally given [14C]-amezinium metilsulfate. Plasma and aorta contained unchanged amezinium and glucuronide of hydroxyl amezinium MIII. In the brain, the major metabolite was O-demethyl amezinium MV and unchanged drug was not detected. Urinary metabolites were largely MIII glucuronide and the unhanged drug. Biliary metabolite was found composed mostly from MIII glucuronide. In feces, MIII and the unchanged amezinium were found. In feces, MIII and the unchanged amezinium were found. MIII and its glucuronide were novel metabolites which were identified by thin-layer chromatography and mass spectrometry.