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.

Rat strain differences in stereospecific 2‐oxidation of RS‐8359, a reversible and selective MAO‐A inhibitor, by aldehyde oxidase

“…Previous metabolic studies on RS-8359 revealed that one of the major metabolic pathways is the stereoselective 2-oxidation of the (S)-enantiomer of RS-8359 catalysed by aldehyde oxidase [7,9]. Marked species differences were shown in enzyme activity, it being much higher in monkeys and humans and deficient in dogs [8,9]. The findings agree with the well-known species differences in aldehyde oxidase [13][14][15][18][19][20].…”

“…Roughly, the degree of aldehyde oxidase activity is high in monkeys and humans, moderate in rats and mice and deficient in dogs. The large species differences shown in the in vivo [8,9] and in vitro [11] metabolism of RS-8359 were highly consistent with those already reported.…”

A Single Amino Acid Substitution Confers High Cinchonidine Oxidation Activity Comparable with That of Rabbit to Monkey Aldehyde Oxidase 1

“…Being fundamentally different from XOR, AOX1-catalyzed drug metabolism results in marked species differences, which have been well documented for methotrexate (Jordan et al, 1999;Kitamura et al, 1999), famciclovir (Rashidi et al, 1997), cinchona alkaloids (Beedham et al, 1992;Itoh et al, 2006), zonisamide (Kitamura et al, 2001), and a monoamine oxidase A inhibitor RS-8359 (Takasaki et al, 1999(Takasaki et al, , 2005Itoh et al, 2005Itoh et al, , 2006. As a rule, AOX1 activity is high in monkeys and humans, moderate to low in rabbits, rats, and mice, and deficient in dogs.…”

Chiral inversion of RS‐8359: A selective and reversible MAO‐A inhibitor via oxido‐reduction of keto‐alcohol

“…Previous metabolic studies on RS-8359 revealed that the (S)-enantiomer of the compound disappeared extremely rapidly from the plasma in every animal species as compared to the (R)-enantiomer after oral administration to rats, mice, dogs, monkeys, and humans. 7,8 The AUC(R)/AUC(S) ratios were 2.6 in rats, 3.8 in mice, 31 in dogs, and 238 in monkeys.7 The (S)-enantiomer was not substantially detected in human plasma. The in vivo and partially in vitro metabolism studies in rats demonstrated that the enantioselective pharmacokinetics might be caused by the enantioselectivity of metabolism, but not intestinal absorption, tissue distribution, and urinary or biliary excretion.…”