Stereoselective pharmacokinetics of RS‐8359, a selective and reversible MAO‐A inhibitor, by species‐dependent drug‐metabolizing enzymes

Abstract

RS‐8359, (±)‐4‐(4‐cyanoanilino)‐5,6‐dihydro‐7‐hydroxy‐7H‐cyclopenta[d]pyrimidine selectively and reversibly inhibits monoamine oxidase A (MAO‐A). After oral administration of rac‐RS‐8359 to rats, mice, dogs, monkeys, and humans, plasma concentrations of the (R)‐enantiomer were greatly higher than were those of the (S)‐enantiomer in all species studied. The AUC_(R) to AUC_(S) ratios were 2.6 in rats, 3.8 in mice, 31 in dogs, and 238 in monkeys, and the (S)‐enantiomer was almost negligible in human plasma. After intravenous administration of RS‐8359 enantiomers to rats, the pharmacokinetic parameters showed that the (S)‐enantiomer had a 2.7‐fold greater total clearance (CL_t) and a 70% shorter half‐life (t_1/2) than those for the (R)‐enantiomer but had no difference in distribution volume (V_d). No significant difference in the intestinal absorption rate was observed. The principal metabolites were the 2‐keto form, possibly produced by aldehyde oxidase, the cis‐diol form, and the 2‐keto‐cis‐diol form produced by cytochrome P450 in rats, the cis‐diol form in mice, RS‐8359 glucuronide in dogs, and the 2‐keto form in monkeys and humans. Thus, the rapid disappearance of the (S)‐enantiomer from the plasma was thought to be due to the rapid metabolism of the (S)‐enantiomer by different drug‐metabolizing enzymes, depending on species. Chirality 17:135–141, 2005.