Pharmacokinetics of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate. 4th communication: metabolism in rats and dogs.

1. The metabolism of NS-21 ((+/-)-4-diethylamino-1, 1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate, CAS 129927-33-4) was investigated in rats and dogs. Only a trace amount of the unchanged drug was excreted into urine and bile. This result indicates that NS-21 is extensively metabolized. 2. Seven metabolites (M-1 to M-7) were isolated from rat urine after oral administration of NS-21. Their chemical structures were confirmed by mass spectrometry and co-chromatography with the authentic compounds. On the basis of these results, we postulate that NS-21 is metabolized through the following 3 pathways; 1) N-deethylation, 2) hydroxylation of the cyclohexyl ring, and 3)hydrolysis of the ester bond. 3. The concentrations of NS-21 and its metabolites in the plasma, liver, kidney and lung were determined after single and repeated oral administrations of 14C-NS-21. The concentrations of the unchanged drug and its N-deethylated metabolite (RCC-36) in the tissues were higher than those in the plasma 1 h after single administration. There were no differences in the tissue concentrations of the unchanged drug between single and repeated administration except in the liver. 4. After oral administration of 14C-NS-21 to urinary-ducts cannulated rats, the concentrations of the unchanged drug and RCC-36 in the bladder, the target organ, were higher than in the plasma.