{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:51:38Z","timestamp":1792068698260,"version":"4.4.0"},"reference-count":39,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Branched\u2010chain amino acids (BCAAs) are essential dietary components that humans cannot synthesize. Altered BCAA levels have been associated with biomarkers or potential risk factors in several metabolic disorders, including insulin resistance, type 2 diabetes, obesity, and cardiovascular disease. However, the underlying mechanisms regulating BCAA metabolism and how cellular or signaling modifications may alter BCAA levels are yet to be fully elucidated. To investigate the fate of plasma and intracellular leucine, we developed a mathematical model of human leucine metabolism. Through a virtual population approach, the model was constructed based on known biology and data and calibrated to fit available acute leucine and \u03b1\u2010ketoisocaproic acid (KIC) clinical challenge data in healthy subjects. The rate\u2010limiting step of BCAA catabolism is oxidative decarboxylation by branched\u2010chain \u03b1\u2010ketoacid dehydrogenase (BCKDH), a process that is negatively regulated by phosphorylation by branched\u2010chain \u03b1\u2010ketoacid dehydrogenase kinase (BDK). Recent preclinical studies have reported that inhibition of BDK leads to significant lowering of plasma BCAA levels. Modeling predicts that the magnitude of reduction observed in plasma BCAA and BCKA levels upon BDK inhibition may require incorporation of an additional regulatory mechanism, such as feedback on leucine and KIC uptake into tissues. This leucine systems model has implications for drug discovery and development, enables a mechanistic understanding of clinical data, and could be used as a tool for the design and analysis of therapeutic modifications of leucine and KIC metabolism.<\/jats:p>","DOI":"10.1002\/psp4.70328","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T03:28:17Z","timestamp":1789702097000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Quantitative Systems Pharmacology Model of Human Leucine Metabolism"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6240-9950","authenticated-orcid":false,"given":"J. 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