Alteration of kynurenic acid concentration in rat plasma following optically pure kynurenine administration: A comparative study between enantiomers

L ‐Kynurenine (KYN), a tryptophan metabolite, is metabolized to kynurenic acid (KYNA), which is an antagonist of N ‐methyl‐ D ‐aspartate and α7 nicotinic acetylcholine receptors, by kynurenine aminotransferase (KAT) I and KAT II. In this study, optically pure KYN, namely L ‐KYN or D ‐KYN, was administered intraperitoneally to male Sprague‐Dawley rats (16.3 μmol kg −1 ), and the change in plasma KYNA was investigated by using column‐switching high‐performance liquid chromatography (HPLC) with fluorescence detection. Unexpectedly, no remarkable alteration in the plasma KYNA was observed when a natural isomer, L ‐KYN, was administered, whereas plasma KYNA concentration was unequivocally increased when an unnatural isomer, D ‐KYN, was administered. Serum protein bindings of L ‐KYN and D ‐KYN were also studied, and the protein binding of L ‐KYN (∼65%) in rat serum was larger than that of D ‐KYN (∼12%), suggesting that D ‐KYN may be easily incorporated and metabolized in tissues during blood circulation to generate KYNA in mammals. In addition, the increase in plasma KYNA by the administration of D ‐KYN was suppressed in rats pretreated with a selective inhibitor of D ‐amino acid oxidase (DAAO), 5‐methylpyrazole‐3‐carboxylic acid (80 mg/kg). These results suggest that DAAO might be responsible for the production of KYNA from D ‐KYN in vivo. Chirality, 2009. © 2008 Wiley‐Liss, Inc.