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Peripheral accumulation of one LNAA (e.g., phenylalanine (phe) in PKU) is predicted to increase uptake of the offending amino acid to the detriment of others, resulting in disruption of brain amino acid homeostasis. We hypothesized that selected non\u2010physiological amino acids (NPAAs) such as DL\u2010norleucine (NL), 2\u2010aminonorbornane (NB; 2\u2010aminobicyclo\u2010(2,1,1)\u2010heptane\u20102\u2010carboxylic acid), 2\u2010aminoisobutyrate (AIB), and N\u2010methyl\u2010aminoisobutyrate (MAIB), acting as competitive inhibitors of various brain amino acid transporters, could reduce brain phe in <jats:italic>Pah<\/jats:italic><jats:sup><jats:italic>enu2<\/jats:italic><\/jats:sup> mice, a relevant murine model of PKU. Oral feeding of 5 % NL, 5 % AIB, 0.5 % NB and 3 % MAIB reduced brain phe by 56 % (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), \u20101 % (<jats:italic>p<\/jats:italic>\u2009=\u2009NS), 27 % (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and 14 % (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), respectively, compared to untreated subjects. Significant effects on other LNAAs (tyrosine, methionine, branched chain amino acids) were also observed, however, with MAIB displaying the mildest effects. Of interest, MAIB represents an inhibitor of the system A (alanine) transporter that primarily traffics small amino acids and not LNAAs. Our studies represent the first in vivo use of these NPAAs in <jats:italic>Pah<\/jats:italic><jats:sup><jats:italic>enu2<\/jats:italic><\/jats:sup> mice, and provide proof\u2010of\u2010principle for their further preclinical development, with the long\u2010term objective of identifying NPAA combinations and concentrations that selectively restrict brain phe transport while minimally impacting other LNAAs and downstream intermediates.<\/jats:p>","DOI":"10.1007\/s10545-012-9524-8","type":"journal-article","created":{"date-parts":[[2012,9,13]],"date-time":"2012-09-13T13:49:10Z","timestamp":1347544150000},"page":"513-523","source":"Crossref","is-referenced-by-count":20,"title":["Non\u2010physiological amino acid (NPAA) therapy targeting brain phenylalanine reduction: pilot studies in <i>PAH<\/i><sup><b><i>ENU2<\/i><\/b><\/sup> mice"],"prefix":"10.1002","volume":"36","author":[{"given":"Kara R.","family":"Vogel","sequence":"first","affiliation":[{"name":"Section of Clinical Pharmacology, College of Pharmacy Washington State University PO Box 646510 313 Wegner Hall Pullman WA 99164\u20106510 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erland","family":"Arning","sequence":"additional","affiliation":[{"name":"Institute of Metabolic Disease, Baylor Research Institute Baylor University Medical Center Dallas TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandi L.","family":"Wasek","sequence":"additional","affiliation":[{"name":"Institute of Metabolic Disease, Baylor Research Institute Baylor University Medical Center Dallas TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodoro","family":"Bottiglieri","sequence":"additional","affiliation":[{"name":"Institute of Metabolic Disease, Baylor Research Institute Baylor University Medical Center Dallas TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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