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Species differences in enantioselective 2‐oxidations of RS‐8359, a selective and reversible MAO‐A inhibitor, and cinchona alkaloids by aldehyde oxidase
Author(s) -
Itoh Kunio,
Yamamura Mayumi,
Takasaki Wataru,
Sasaki Takamitsu,
Masubuchi Akiko,
Tanaka Yorihisa
Publication year - 2006
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.494
Subject(s) - aldehyde oxidase , enantiomer , chemistry , metabolite , aldehyde , cinchonidine , cinchona alkaloids , stereochemistry , in vivo , enantioselective synthesis , biochemistry , enzyme , biology , catalysis , xanthine oxidase , microbiology and biotechnology
The 2‐oxidation activity on the pyrimidine ring of RS‐8359, a MAO‐A inhibitor, is the major metabolic pathway catalysed by aldehyde oxidase. This study investigated the species differences in the 2‐oxidation activity by using liver cytosolic fractions from rats, mice, guinea‐pigs, rabbits, dogs, monkeys and humans. The V max / K m value for the ( S )‐enantiomer of RS‐8359 was extremely high in monkeys and humans, moderate in guinea‐pigs, and low in rats and mice. Dogs were deficient in 2‐oxidation activity. The ( R )‐enantiomer was only oxidized at a very low rate in guinea‐pigs, monkeys and humans, and not oxidized in rats, mice and rabbits. Thus, marked species differences and enantioselectivity were obvious for the 2‐oxidation of the ( S )‐enantiomer of RS‐8359. The in vitro results were in good accordance with previously reported in vivo excretion data of the 2‐keto metabolite and the non‐detectable plasma concentrations of the ( S )‐enantiomer in monkeys and humans after administration of racemic RS‐8359. Enantioselectivity was also observed for the oxidation of cinchona alkaloids catalysed by aldehyde oxidase. Among the four cinchona alkaloids studied, the oxidation activity of cinchonidine, which has no substituents at the 6‐hydroxy group but bears ( 8S,9R )‐configurations, was highest. As opposed to the ( S )‐enantiomer, an extremely high catalytic activity of cinchonidine was confirmed in rabbits, but not in monkeys or humans. Rabbit liver aldehyde oxidase was suggested to have characteristic properties around the active site. Copyright © 2006 John Wiley & Sons, Ltd.