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Enantioselective 2‐hydroxylation of RS‐8359, a selective and reversible MAO‐A inhibitor, by cytochrome P450 in mouse and rat liver microsomes
Author(s) -
Itoh Kunio,
Nishiya Yumi,
Takasaki Wataru,
Adachi Mayuko,
Tanaka Yorihisa
Publication year - 2006
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.20291
Subject(s) - metabolite , enantiomer , chemistry , hydroxylation , stereochemistry , microsome , diol , enantioselective synthesis , cytochrome p450 , stereoisomerism , metabolism , enzyme , biochemistry , organic chemistry , catalysis
RS‐8359, (±)‐4‐(4‐cyanoanilino)‐5,6‐dihydro‐7‐hydroxy‐7 H ‐cyclopenta[ d ]‐pyrimidine is a racemic compound with a selective and reversible monoamine oxidase A (MAO‐A) inhibition activity. The substrate and product enantioselectivity with respect to 2‐hydroxylation of RS‐8359 enantiomers was studied using mouse and rat liver microsomes. In mice, the ( S )‐enantiomer was transformed to the cis ‐diol metabolite, whereas the ( R )‐enantiomer to the trans ‐diol metabolite. The V max/ K m value for the formation of the cis ‐diol metabolite from the ( S )‐enantiomer was sevenfold greater than that for the formation of the trans ‐diol metabolite from the ( R )‐enantiomer. The greater V max/ K m value for the ( S )‐enantiomer was due to the tenfold smaller K m value compared to that for the ( R )‐enantiomer. The results were in fair agreement with the previously reported low plasma concentrations of the ( S )‐enantiomer and the high recovery of the cis ‐diol metabolite derived from the ( S )‐enantiomer in urine after oral administration of RS‐8359 to mice. Similarly to mice, in rats the ( R )‐enantiomer was transformed to the trans ‐diol metabolite, whereas the ( S )‐enantiomer yielded the cis ‐diol and trans ‐diol metabolites. The V max/ K m value for the ( R )‐enantiomer was larger than that for the ( S )‐enantiomer in rats, indicating that the low plasma concentration of the ( S )‐enantiomer in rats might be caused by a metabolic reaction other than P450‐dependent hydroxylation. CYP3A was shown to be responsible for the trans ‐diol formation from the ( R )‐enantiomer. Chirality, 2006. © 2006 Wiley‐Liss, Inc.