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 were studied during and after repeated oral administration of 30 mg/kg of 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 14C-NS-21 reached a steady state on the 5th day. 48 h after the 21st administration, the plasma concentrations of radioactivity were under the detection limit. The plasma concentrations of the radioactivity after the 7th oral administration of 14C-NS-21 was higher than that after the single administration, but similar to those after the 14th and 21st administrations. There were no marked differences in the elimination half-lives after each administration. The urinary and fecal excretion of the radioactivity was 21.5 and 81.3%, respectively, within 168 h after the 21st administration. In most tissues, no radioactivity was observed 336 h after the 21st administration. 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, aniline hydroxylase and aminopyrine N-demethylase activity in rat liver. The transfer of radioactivity into fetuses and milk was investigated after single oral administration of 14C-NS-21 to female rats. In the 18th day pregnant rats, the radioactivity concentrations were lower in most fetal tissues than in the maternal plasma. After oral administration of 14C-NS-21 to lactating rats, the concentrations of radioactivity were higher in the milk than in the maternal plasma during an 8-h period. No radioactivity was observed in milk 48 h after administration.