title: Physiological Competition of Brain Phenylalanine Accretion: Initial Pharmacokinetic Analyses of Aminoisobutyric and Methylaminoisobutyric Acids inPahenu2-/-Mice.
abstract: OBJECTIVE
  Initial studies on the use of non-physiological amino acids (NPAAs) to block the accretion of Phe in the brainPahenu2-/-mice revealed that 2-aminoisobutyrate (AIB) andN-methyl-2-aminoisobutyrate (MAIB) were promising lead compounds whose pharmacokinetic parameters warranted investigation.
  
  
  METHODS
  Control andPahenu2-/-mice received intraperitoneal NPAA treatments as test compounds (150, 300 and 500 mg/kg, 1 or 7 days;) followed by collection of sera, liver and brain. LC-MS analysis was developed to quantify both AIB and MAIB in all matrices, and pharmacokinetic parameters for distribution, partitioning, accumulation and MAIB demethylation were determined.
  
  
  RESULTS
  MAIB was partially converted to AIBin vivo. AIB and MAIB partitioned similarly from sera to brain and liver, with an approximate 10-fold higher accumulation in liver compared to brain. In comparison to MAIB, AIB accumulated to approximately 3 to 7-fold higher concentration in brain. Analysis of brain and liver revealed a trend toward decreased Phe with increased MAIB sera concentration.
  
  
  CONCLUSIONS
  Our data support further pharmacokinetic characterization of MAIB and AIB in preparation for further preclinical safety, toxicity and tolerability studies of both AIB and MAIB.
authors.affiliation: Section of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, WA.
authors.forename: Kara R
authors.initials: KR
authors.lastname: Vogel
authors.affiliation: Section of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, WA.
authors.forename: Garrett R
authors.initials: GR
authors.lastname: Ainslie
authors.affiliation: Departments of Pharmaceutics and Pharmacy, University of Washington School of Pharmacy, Seattle, WA.
authors.forename: Brian
authors.initials: B
authors.lastname: Phillips
authors.affiliation: Institute for Metabolic Disease, Baylor Research Institute, Dallas, TX.
authors.forename: Erland
authors.initials: E
authors.lastname: Arning
authors.affiliation: Institute for Metabolic Disease, Baylor Research Institute, Dallas, TX.
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.affiliation: Departments of Pharmaceutics and Pharmacy, University of Washington School of Pharmacy, Seattle, WA.
authors.forename: Danny D
authors.initials: DD
authors.lastname: Shen
authors.affiliation: Section of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, WA.
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
keywords: Aminoisobutyric Acid; LAT-1 Transporter; Large Neutral Amino Acids; Methylaminoisobutyric Acid; Pharmacokinetics; Phenylalanine; Phenylketonuria