PHARMACOKINETICS OF (+ -)-4-DIETHYLAMINO-1,1-DIMETHYLBUT-2-YN-1-YL 2-CYCLOHEXYL-2-HYDROXY-2-PHENYLACETATE MONOHYDROCHLORIDE MONOHYDRATE - 3RD COMMUNICATION - PLASMA-CONCENTRATIONS OF THE UNCHANGED DRUG AND ITSDEETHYLATED METABOLITE IN RATS, DOGS AND MONKEYS/

1. The plasma concentrations of NS-21 ((+/-)-4-diehtylamino-1,1-dimeth ylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochlori de monohydrate, CAS 129927-33-4) and its deethylated metabolite (RCC-3 6) after intravenous and oral administrations of (S/R)-NS-21 were meas ured in rats, dogs and monkeys. After intravenous administration, the plasma concentrations of NS-21 decreased biexponentially. The half-liv es of NS-21 in the elimination phase were 2.2 h in rats, 5.3 h in dogs and 15.4 h in monkeys. After oral administration, the systemic availa bilities were 4 % in rats, 22 % in dogs and 6 % in monkeys. After intr avenous administration, the plasma concentrations of RCC-36 were much lower than those of the unchanged drug in all the animal species teste d. In contrast, after oral administration, the plasma concentrations o f RCC-36 were comparable to those of the unchanged drug in rats and do gs, and were higher in monkeys. This result suggests that RCC-36 is ma inly produced by the first-pass effect. 2. The plasma concentrations o f NS-21 and RCC-36 after intravenous and oral administrations of (S)- or (R)-NS-21 were measured in dogs. The AUC value of the unchanged dru g after intravenous administration of (R)-NS-21 was about twice as lar ge as that of (S)-NS-21. After oral administration, the systemic avail abilities of (S)- and (R)-NS-21 were 17 and 22 %, respectively. There were no differences in the serum binding between (S)- and (R)-NS-21 in any of the animal species tested including humans. (S)- and (R)NS-21 were mainly converted to RCC-36 and a 4-cyclohydroxylated metabolite ( NS-21-4-OH) in hepatic microsomes of rats, dogs and monkeys. There wer e no marked differences in the N-deethylation of (S)- and (R)-NS-21 in all the animals. In contrast, (S)-NS-21 was converted to NS-21-4-OH m ore preferentially than (R)-NS-21 only in dogs. These findings indicat e that the stereo-selective disposition of NS-21 in dogs is due to the stereo-selective cyclohydroxylation of NS-21.