TY - JOUR T1 - Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.118.111625 SP - mol.118.111625 AU - Cheng Chang AU - Kari R Fonseca AU - Cheryl Li AU - Weldon Horner AU - Laura Zawadzke AU - Michelle A Salafia AU - Kathryn A Welch AU - Christine Strick AU - Brian Campbell AU - Steven Gernhardt AU - Haojing Rong AU - Aarti Sawant-Basak AU - Jenney Liras AU - Amy Dounay AU - Jamison B Tuttle AU - Patrick R Verhoest AU - Tristan S Maurer Y1 - 2018/01/01 UR - http://molpharm.aspetjournals.org/content/early/2018/05/31/mol.118.111625.abstract N2 - Kynurenic acid (KYNA) plays a significant role in maintaining normal brain function and abnormalities in KYNA levels have been associated with various central nervous system disorders. Confirmation of its causality in human diseases requires safe and effective modulation of central KYNA levels in the clinic. The kynurenine aminotransferases II (KAT II) enzyme represents an attractive target for pharmacological modulation of central KYNA levels. However, KAT II and KYNA turnover kinetics, which could contribute to the duration of pharmacological effect, have not been reported. In this study, the kinetics of central KYNA lowering effect in rat and non-human primate (NHP) were investigated using multiple KAT II irreversible inhibitors as pharmacological probes. Mechanistic pharmacokinetic pharmacodynamic (PKPD) analysis of in vivo responses to irreversible inhibition quantitatively revealed 1) KAT II turnover is relatively slow while KYNA is more rapidly cleared from brain in both rat and NHP; 2) KAT II turnover is slower in NHP than in rat; 3) Percent contribution of KAT II to KYNA formation is constant (~80%) across rat and NHP. Additionally, modeling results enabled establishment of in vitro-in vivo correlation (IVIVC) for both enzyme turnover rates and drug potencies. In summary, quantitative translational analysis confirmed feasibility of central KYNA modulation in human. Model-based analysis, where system-specific properties and drug-specific properties are mechanistically separated from in vivo responses, enabled quantitative understanding of KAT II - KYNA pathway as well as assisted development of promising candidates to test KYNA hypothesis in humans. ER -