PHARMACOKINETICS OF (+ -)-4-DIETHYLAMINO-1,1-DIMETHYLBUT-2-YN-1-YL 2-CYCLOHEXYL-2-HYDROXY-2-PHENYLACETATE MONOHYDROCHLORIDE MONOHYDRATE 4THCOMMUNICATION - 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 monohydr ate, 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 re sult indicates that NS-21 is extensively metabolized. 2. Seven metabol ites (M-1 to M-7) were isolated from rat urine after oral administrati on of NS-21. Their chemical structures were confirmed by mass spectrom etry and cochromatography with the authentic compounds. On the basis o f these results, we postulate that NS-21 is metabolized through the fo llowing 3 pathways; 1) N-deethylation, 2) hydroxylation of the cyclohe xyl ring, and 3) hydrolysis of the ester bond. 3. The concentrations o f NS-21 and its metabolites in the plasma, liver, kidney and lung were determined after single and repeated oral administrations of C-14-NS- 21. The concentrations of the unchanged drug and its N-deethylated met abolite (RCC-36) in the tissues were higher than those in the plasma 1 h after single administration. There were no differences in the tissu e concentrations of the unchanged drug between single and repeated adm inistration except in the liver. 4. After oral administration of C-14- NS-21 to urinary-ducts cannulated rats, the concentrations of the unch anged drug and RCC-36 in the bladder, the target organ, were higher th an in the plasma.