title: Stereoselective pharmacokinetics of RS-8359, a selective and reversible inhibitor of A-type monoamine oxidase, in rats, mice, dogs, and monkeys.
abstract: RS-8359, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-py rimidine, 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]-enantiomer 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] chiral 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.
authors.affiliation: Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: W
authors.initials: W
authors.lastname: Takasaki
authors.forename: M
authors.initials: M
authors.lastname: Yamamura
authors.forename: E
authors.initials: E
authors.lastname: Shigehara
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Tonohiro
authors.forename: T
authors.initials: T
authors.lastname: Hara
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D000882:Haplorhini; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D009570:Nitriles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011743:Pyrimidines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D013045:Species Specificity; D013237:Stereoisomerism
chemical_list: D008996:Monoamine Oxidase Inhibitors; D009570:Nitriles; D011743:Pyrimidines; C059590:RS 8359; D008995:Monoamine Oxidase