Pharmacokinetics of amezinium in man.

Pharmacokinetics of 4-amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, was studied in two groups of subjects. The substance was administered i.v. (1 mg and 10 mg) and p.o. (40 mg and 50 mg), resp. In all cases the time course of renal excretion rate was followed; in two studies blood levels were determined additionally. Together with findings from animal experiments the results are used to describe the pharmacokinetic behaviour of amezinium in man at the present state of knowledge: 1. Absorption of amezinium administered p.o. is preceded by a lag phase which depends on the dissolution time of the tablets used. After the lag phase absorption takes place with a half-life of less than 30 min. 2. Absolute bioavailability of the batches used is estimated to be about 50% and 67% resp. 3. Amezinium is distributed rapidly into the tissues. The first distribution phase detectable has a half-life of less than 10 min. Steady state volumes of distribution are calculated to be between 2 and 3 l/kg. 4. Amezinium and its metabolites are excreted predominantly by the kidneys; extrarenal elimination amounts to about 30%. Terminal half-life was determined from blood levels and excretion data after i.v. as well as p.o. administration to be between 9 and 17 h. 5. Renal clearance of amezinium is not constant. Initially it exceeds the glomerular filtration rate (GFR) by a factor of 4, later it decreases to values similar to the GFR. Comparison of the time courses of the renal excretion on the one hand and of the blood level on the other indicates that renal handling of amezinium may be influenced by its own pharmacological action. This anomalous clearance behaviour of amezinium is considered to be favourable with respect to drug safety.