Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition [Articles]

Publication Date:
2018-06-27
Publisher:
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
Print ISSN:
0026-895X
Electronic ISSN:
1521-0111
Topics:
Chemistry and Pharmacology
Medicine
Published by:
http://www.aspet.org/
_version_ 1836398987064639488
autor Chang, C., Fonseca, K. R., Li, C., Horner, W., Zawadzke, L. E., Salafia, M. A., Welch, K. A., Strick, C. A., Campbell, B. M., Gernhardt, S. S., Rong, H., Sawant-Basak, A., Liras, J., Dounay, A., Tuttle, J. B., Verhoest, P., Maurer, T. S.
beschreibung 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 (KAT) II enzyme represents an attractive target for pharmacologic modulation of central KYNA levels; however, KAT II and KYNA turnover kinetics, which could contribute to the duration of pharmacologic effect, have not been reported. In this study, the kinetics of central KYNA-lowering effect in rats and nonhuman primates (NHPs, Cynomolgus macaques ) was investigated using multiple KAT II irreversible inhibitors as pharmacologic probes. Mechanistic pharmacokinetic-pharmacodynamic analysis of in vivo responses to irreversible inhibition quantitatively revealed that 1) KAT II turnover is relatively slow [16–76 hours’ half-life ( t 1/2 )], whereas KYNA is cleared more rapidly from the brain (〈1 hour t 1/2 ) in both rats and NHPs, 2) KAT II turnover is slower in NHPs than in rats (76 hours vs. 16 hours t 1/2 , respectively), and 3) the percent contribution of KAT II to KYNA formation is constant (~80%) across rats and NHPs. Additionally, modeling results enabled establishment of in vitro-in vivo correlation for both enzyme turnover rates and drug potencies. In summary, quantitative translational analysis confirmed the feasibility of central KYNA modulation in humans. Model-based analysis, where system-specific properties and drug-specific properties are mechanistically separated from in vivo responses, enabled quantitative understanding of the KAT II-KYNA pathway, as well as assisted development of promising candidates to test KYNA hypothesis in humans.
citation_standardnr 6292959
datenlieferant ipn_articles
feed_id 1938
feed_publisher The American Society for Pharmacology and Experimental Therapeutics (ASPET)
feed_publisher_url http://www.aspet.org/
insertion_date 2018-06-27
journaleissn 1521-0111
journalissn 0026-895X
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Society for Pharmacology and Experimental Therapeutics (ASPET)
quelle Molecular Pharmacology
relation http://molpharm.aspetjournals.org/cgi/content/short/94/2/823?rss=1
search_space articles
shingle_author_1 Chang, C., Fonseca, K. R., Li, C., Horner, W., Zawadzke, L. E., Salafia, M. A., Welch, K. A., Strick, C. A., Campbell, B. M., Gernhardt, S. S., Rong, H., Sawant-Basak, A., Liras, J., Dounay, A., Tuttle, J. B., Verhoest, P., Maurer, T. S.
shingle_author_2 Chang, C., Fonseca, K. R., Li, C., Horner, W., Zawadzke, L. E., Salafia, M. A., Welch, K. A., Strick, C. A., Campbell, B. M., Gernhardt, S. S., Rong, H., Sawant-Basak, A., Liras, J., Dounay, A., Tuttle, J. B., Verhoest, P., Maurer, T. S.
shingle_author_3 Chang, C., Fonseca, K. R., Li, C., Horner, W., Zawadzke, L. E., Salafia, M. A., Welch, K. A., Strick, C. A., Campbell, B. M., Gernhardt, S. S., Rong, H., Sawant-Basak, A., Liras, J., Dounay, A., Tuttle, J. B., Verhoest, P., Maurer, T. S.
shingle_author_4 Chang, C., Fonseca, K. R., Li, C., Horner, W., Zawadzke, L. E., Salafia, M. A., Welch, K. A., Strick, C. A., Campbell, B. M., Gernhardt, S. S., Rong, H., Sawant-Basak, A., Liras, J., Dounay, A., Tuttle, J. B., Verhoest, P., Maurer, T. S.
shingle_catch_all_1 Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition [Articles]
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 (KAT) II enzyme represents an attractive target for pharmacologic modulation of central KYNA levels; however, KAT II and KYNA turnover kinetics, which could contribute to the duration of pharmacologic effect, have not been reported. In this study, the kinetics of central KYNA-lowering effect in rats and nonhuman primates (NHPs, Cynomolgus macaques ) was investigated using multiple KAT II irreversible inhibitors as pharmacologic probes. Mechanistic pharmacokinetic-pharmacodynamic analysis of in vivo responses to irreversible inhibition quantitatively revealed that 1) KAT II turnover is relatively slow [16–76 hours’ half-life ( t 1/2 )], whereas KYNA is cleared more rapidly from the brain (<1 hour t 1/2 ) in both rats and NHPs, 2) KAT II turnover is slower in NHPs than in rats (76 hours vs. 16 hours t 1/2 , respectively), and 3) the percent contribution of KAT II to KYNA formation is constant (~80%) across rats and NHPs. Additionally, modeling results enabled establishment of in vitro-in vivo correlation for both enzyme turnover rates and drug potencies. In summary, quantitative translational analysis confirmed the feasibility of central KYNA modulation in humans. Model-based analysis, where system-specific properties and drug-specific properties are mechanistically separated from in vivo responses, enabled quantitative understanding of the KAT II-KYNA pathway, as well as assisted development of promising candidates to test KYNA hypothesis in humans.
Chang, C., Fonseca, K. R., Li, C., Horner, W., Zawadzke, L. E., Salafia, M. A., Welch, K. A., Strick, C. A., Campbell, B. M., Gernhardt, S. S., Rong, H., Sawant-Basak, A., Liras, J., Dounay, A., Tuttle, J. B., Verhoest, P., Maurer, T. S.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0026-895X
0026895X
1521-0111
15210111
shingle_catch_all_2 Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition [Articles]
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 (KAT) II enzyme represents an attractive target for pharmacologic modulation of central KYNA levels; however, KAT II and KYNA turnover kinetics, which could contribute to the duration of pharmacologic effect, have not been reported. In this study, the kinetics of central KYNA-lowering effect in rats and nonhuman primates (NHPs, Cynomolgus macaques ) was investigated using multiple KAT II irreversible inhibitors as pharmacologic probes. Mechanistic pharmacokinetic-pharmacodynamic analysis of in vivo responses to irreversible inhibition quantitatively revealed that 1) KAT II turnover is relatively slow [16–76 hours’ half-life ( t 1/2 )], whereas KYNA is cleared more rapidly from the brain (<1 hour t 1/2 ) in both rats and NHPs, 2) KAT II turnover is slower in NHPs than in rats (76 hours vs. 16 hours t 1/2 , respectively), and 3) the percent contribution of KAT II to KYNA formation is constant (~80%) across rats and NHPs. Additionally, modeling results enabled establishment of in vitro-in vivo correlation for both enzyme turnover rates and drug potencies. In summary, quantitative translational analysis confirmed the feasibility of central KYNA modulation in humans. Model-based analysis, where system-specific properties and drug-specific properties are mechanistically separated from in vivo responses, enabled quantitative understanding of the KAT II-KYNA pathway, as well as assisted development of promising candidates to test KYNA hypothesis in humans.
Chang, C., Fonseca, K. R., Li, C., Horner, W., Zawadzke, L. E., Salafia, M. A., Welch, K. A., Strick, C. A., Campbell, B. M., Gernhardt, S. S., Rong, H., Sawant-Basak, A., Liras, J., Dounay, A., Tuttle, J. B., Verhoest, P., Maurer, T. S.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0026-895X
0026895X
1521-0111
15210111
shingle_catch_all_3 Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition [Articles]
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 (KAT) II enzyme represents an attractive target for pharmacologic modulation of central KYNA levels; however, KAT II and KYNA turnover kinetics, which could contribute to the duration of pharmacologic effect, have not been reported. In this study, the kinetics of central KYNA-lowering effect in rats and nonhuman primates (NHPs, Cynomolgus macaques ) was investigated using multiple KAT II irreversible inhibitors as pharmacologic probes. Mechanistic pharmacokinetic-pharmacodynamic analysis of in vivo responses to irreversible inhibition quantitatively revealed that 1) KAT II turnover is relatively slow [16–76 hours’ half-life ( t 1/2 )], whereas KYNA is cleared more rapidly from the brain (<1 hour t 1/2 ) in both rats and NHPs, 2) KAT II turnover is slower in NHPs than in rats (76 hours vs. 16 hours t 1/2 , respectively), and 3) the percent contribution of KAT II to KYNA formation is constant (~80%) across rats and NHPs. Additionally, modeling results enabled establishment of in vitro-in vivo correlation for both enzyme turnover rates and drug potencies. In summary, quantitative translational analysis confirmed the feasibility of central KYNA modulation in humans. Model-based analysis, where system-specific properties and drug-specific properties are mechanistically separated from in vivo responses, enabled quantitative understanding of the KAT II-KYNA pathway, as well as assisted development of promising candidates to test KYNA hypothesis in humans.
Chang, C., Fonseca, K. R., Li, C., Horner, W., Zawadzke, L. E., Salafia, M. A., Welch, K. A., Strick, C. A., Campbell, B. M., Gernhardt, S. S., Rong, H., Sawant-Basak, A., Liras, J., Dounay, A., Tuttle, J. B., Verhoest, P., Maurer, T. S.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0026-895X
0026895X
1521-0111
15210111
shingle_catch_all_4 Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition [Articles]
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 (KAT) II enzyme represents an attractive target for pharmacologic modulation of central KYNA levels; however, KAT II and KYNA turnover kinetics, which could contribute to the duration of pharmacologic effect, have not been reported. In this study, the kinetics of central KYNA-lowering effect in rats and nonhuman primates (NHPs, Cynomolgus macaques ) was investigated using multiple KAT II irreversible inhibitors as pharmacologic probes. Mechanistic pharmacokinetic-pharmacodynamic analysis of in vivo responses to irreversible inhibition quantitatively revealed that 1) KAT II turnover is relatively slow [16–76 hours’ half-life ( t 1/2 )], whereas KYNA is cleared more rapidly from the brain (<1 hour t 1/2 ) in both rats and NHPs, 2) KAT II turnover is slower in NHPs than in rats (76 hours vs. 16 hours t 1/2 , respectively), and 3) the percent contribution of KAT II to KYNA formation is constant (~80%) across rats and NHPs. Additionally, modeling results enabled establishment of in vitro-in vivo correlation for both enzyme turnover rates and drug potencies. In summary, quantitative translational analysis confirmed the feasibility of central KYNA modulation in humans. Model-based analysis, where system-specific properties and drug-specific properties are mechanistically separated from in vivo responses, enabled quantitative understanding of the KAT II-KYNA pathway, as well as assisted development of promising candidates to test KYNA hypothesis in humans.
Chang, C., Fonseca, K. R., Li, C., Horner, W., Zawadzke, L. E., Salafia, M. A., Welch, K. A., Strick, C. A., Campbell, B. M., Gernhardt, S. S., Rong, H., Sawant-Basak, A., Liras, J., Dounay, A., Tuttle, J. B., Verhoest, P., Maurer, T. S.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0026-895X
0026895X
1521-0111
15210111
shingle_title_1 Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition [Articles]
shingle_title_2 Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition [Articles]
shingle_title_3 Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition [Articles]
shingle_title_4 Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition [Articles]
timestamp 2025-06-30T23:35:48.412Z
titel Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition [Articles]
titel_suche Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition [Articles]
topic V
WW-YZ
uid ipn_articles_6292959