Pharmacokinetics of amezinium in rat and dog

Using 14C-labelled 4-amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), briefly called amezinium, the time course of plasma level in the rat and of blood level and renal excretion rate in the dog has been followed. The distribution of radioactivity in the organism was investigated by autoradiography of whole-animal sections and by quantitative radioactivity determinations in rat tissue as well as by in vitro experiments. From the results we draw the following conclusions: 1. In the two species investigated here, amezinium is almost completely absorbed after enteral administration. In the rat the absorption proceeds with a half-life of 11 min, after a lag phase of 6 min. In the dog, the lag phase is 30-40 min, after which the compound is absorbed with a half-life of 30 min or less. The small intestine appears to be the site of absorption. 2. Amezinium has a high affinity for tissues. Its transport through the cell membrane, in the case of sympathetic neurons and probably also in the case of other chromaffin cells, is mediated by the noradrenaline carrier; in other tissues, for example the liver, a different active transport mechanism, as yet not elucidated, is operating. The placenta and blood-brain barrier are passed only slightly, if at all. In rat blood amezinium distributes between erythrocytes and plasma with a ratio of 2.7:1; the proportion bound to plasma proteins is about 20%. 3. In the rat amezinium is eliminated from the circulation to the extent of about 3/4 by biotransformation; on enteral administration, about 80% is trapped by first-pass metabolism. In the dog biotransformation accounting for about 40% of the elimination is relatively unimportant; the first-pass metabolism is virtually negligible. 4. Amezinium is eliminated by rats about equally with urine and bile, whilst in the dog the predominant proportion is excreted renally. From plasma level curves the terminal half-life t 1/2 (beta) in the rat was found to be 17 h and 21 h after i.v. and p.o. administration, respectively; blood level data and urinary excretion data in the case of the dog gave 5 1/2 (beta) values between 11 h and 20 h. 5. Renal clearance of amezinium in the dog is not constant: initially it is several times greater than the glomerular filtration rate (GFR) decreasing subsequently to about the same magnitude or even below the GFR.