PHARMACOKINETICS OF (+ -)-4-DIETHYLAMINO-1,1-DIMETHYLBUT-2-YN-1-YL 2-CYCLOHEXYL-2-HYDROXY-2-PHENYLACETATE MONOHYDROCHLORIDE MONOHYDRATE - 2ND COMMUNICATION - TISSUE-LEVELS AND ENZYME-ACTIVITY IN RATS AFTER REPEATED ADMINISTRATION, AND PLACENTAL AND MILK TRANSFER AFTER SINGLE ADMINISTRATION/

The absorption, distribution and excretion of radioactivity in rats we re studied during and after repeated oral administration of 30 mg/kg o f NS-21 ((+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2 -hydroxy-2-phenylacetate monohydrochloride monohydrate, CAS 129927-33- 4) once a day for 21 days. The plasma concentrations of radioactivity 24 h after each administration of C-14-NS-21 reached a steady state on the 5th day. 48 h after the 21st administration, the plasma concentra tions of radioactivity were under the detection limit. The plasma conc entrations of the radioactivity after the 7th oral administration of C -14-NS-21 was higher than that after the single administration, but si milar to these after the 14th and 21st administrations. There were no marked differences in the elimination half-lives after each administra tion. The urinary and fecal excretion of the radioactivity was 21.5 an d 81.3 %, respectively, within 168 h after the 21st administration. In most tissues. no radioactivity was observed 336 h after the 21st admi nistration. Repeated oral administration of 30 and 100 mg/kg of NS-21 once a day for 7 days had no effect on the cytochrome P-450 content, a niline hydroxylase and aminopyrine N-demethylase activity in rat liver . The transfer of radioactivity into fetuses and milk was investigated after single oral administration of C-14-NS-21 to female rats. In the 18th day pregnant rats, the radioactivity concentrations were lower i n most fetal tissues than in the maternal plasma. After oral administr ation of C-14-NS-21 to lactating rats, the concentrations of radioacti vity were higher in the milk than in the maternal plasma during an 8-h period. No radioactivity was observed in milk 48 h after administrati on.