Enantioselective 2-hydroxylation of RS-8359, a selective and reversible MAO-A inhibitor, by cytochrome P450 in mouse and rat liver microsomes.
RS-8359, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-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 Vmax/Km 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 Vmax/Km value for the (S)-enantiomer was due to the tenfold smaller Km 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 Vmax/Km 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.
Itoh
Kunio
K
Department of Biopharmaceutics, Tohoku Pharmaceutical University, Sendai, Japan.
Nishiya
Yumi
Y
Takasaki
Wataru
W
Adachi
Mayuko
M
Tanaka
Yorihisa
Y
D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006900:Hydroxylation; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism*; D015394:Molecular Structure; D008996:Monoamine Oxidase Inhibitors / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D009570:Nitriles / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013237:Stereoisomerism
D008996:Monoamine Oxidase Inhibitors; D009570:Nitriles; D011743:Pyrimidines; C059590:RS 8359; D003577:Cytochrome P-450 Enzyme System