摘要：RS-8359, (±)-4-(4-cyanoanilino)-5, 6-dihydro-7-hydroxy-7H-cyclopenta[d]-pyrimidine, inhibits, selectively and reversely, A-type monoamine oxidase (MAO-A). In order to clarify the stereoselective metabolism of this drug, plasma concentrations of the [R] and [S]-enantiomers of RS-8359 were determined by chiral column HPLC after oral administration of each enantiomer to rats, mice, dogs, and monkeys. After administration of the [R]-enantiomer, high levels were retained in all animal species studied. On the other hand, when the [S]-enantiomer was administered, plasma concentrations decreased rapidly in rats and mice, and extremely rapidly in dogs, while in monkeys, only a trace amount was detected immediately after dosing. Thus, it was found, as a common phenomenon in rats, mice, dogs, and monkeys, that plasma concentrations of the [S]-enentiomer were markedly lower than those of the [R]-enantiomer. Secondly, the [R]-enantiomer was observed in plasma after administration of the [S]-enantiomer, and the [S] to [R] chiral inversion rate was estimated from AUC([R] after[S])/AUC([R] after [R]). The percentage was 45.8% in rats, 3.8% in mice, 0.8% in dogs, and 4.2% in monkeys.Further, the [S]-enantiomer was detected in plasma of SD rats dosed with the [R]-enantiomer, suggesting [R] to[S] shiral inversion in rats. These results show marked species differences in the chiral inversion of the cyclopentanol group of RS-8359. A mechanism of chiral inversion is discussed based on experiments using isolated rat hepatocytes.
