Stereoselective pharmacokinetics of RS-8359, a selective and reversible MAO-A inhibitor, by species-dependent drug-metabolizing enzymes.
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.
Takasaki
Wataru
W
Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Yamamura
Mayumi
M
Nozaki
Akiko
A
Nitanai
Takashi
T
Sasahara
Kunihiro
K
Itoh
Kunio
K
Tanaka
Yorihisa
Y
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004285:Dogs; D006801:Humans; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008996:Monoamine Oxidase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D009570:Nitriles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013237:Stereoisomerism
D008996:Monoamine Oxidase Inhibitors; D009570:Nitriles; D011743:Pyrimidines; C059590:RS 8359