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 its deethylated metabolite in rats, dogs and monkeys.

1. The plasma concentrations of NS-21 ((+/-)-4-diehtylamino-1, 1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate, CAS 129927-33-4) and its deethylated metabolite (RCC-36) after intravenous and oral administrations of (S/R)-NS-21 were measured in rats, dogs and monkeys. After intravenous administration, the plasma concentrations of NS-21 decreased biexponentially. The half-lives 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 availabilities were 4% in rats, 22% in dogs and 6% in monkeys. After intravenous administration, the plasma concentrations of RCC-36 were much lower than those of the unchanged drug in all the animal species tested. In contrast, after oral administration, the plasma concentrations of RCC-36 were comparable to those of the unchanged drug in rats and dogs, and were higher in monkeys. This result suggests that RCC-36 is mainly produced by the first-pass effect. 2. The plasma concentrations of 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 drug after intravenous administration of (R)-NS-21 was about twice as large as that of (S)-NS-21. After oral administration, the systemic availabilities 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 were 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 more preferentially than (R)-NS-21 only in dogs. These findings indicate that the stereo-selective disposition of NS-21 in dogs is due to the stereo-selective cyclohydroxylation of NS-21.