Enantioselective 2-hydroxylation of RS-8359, a selective and reversible MAO-A inhibitor, by cytochrome P450 in mouse and rat liver microsomes

• Published in: Chirality (New York, N.Y.) Vol. 18; no. 8; pp. 592 - 598
• Main Authors: Itoh, Kunio, Nishiya, Yumi, Takasaki, Wataru, Adachi, Mayuko, Tanaka, Yorihisa
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 2006
• Subjects: Animals; Biotransformation; Cytochrome P-450 Enzyme System - metabolism; enantioselectivity; Hydroxylation; Male; MAO-A inhibitor; Mice; Mice, Mutant Strains; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; Molecular Structure; Monoamine Oxidase Inhibitors - blood; Monoamine Oxidase Inhibitors - chemistry; Monoamine Oxidase Inhibitors - metabolism; Monoamine Oxidase Inhibitors - pharmacokinetics; mouse; Nitriles - blood; Nitriles - chemistry; Nitriles - metabolism; Nitriles - pharmacokinetics; P450; P450, MAO‐A inhibitor; Pyrimidines - blood; Pyrimidines - chemistry; Pyrimidines - metabolism; Pyrimidines - pharmacokinetics; rat; Rats; Rats, Wistar; RS-8359; species difference; Species Specificity; Stereoisomerism
• ISSN: 0899-0042; 1520-636X
• DOI: 10.1002/chir.20291

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. Chirality, 2006. © 2006 Wiley‐Liss, Inc.