physiological competition of brain phenylalanine accretion: initial pharmacokinetic analyses of aminoisobutyric and methylaminoisobutyric acids in pahenu2−/− mice
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ID: 180639
2015
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Abstract
Objective: Initial studies on the use of non-physiological amino acids (NPAAs) to block the accretion of Phe in the brain of Pahenu2−/− mice revealed that 2-aminoisobutyrate (AIB) and N-methyl-2-aminoisobutyrate (MAIB) were promising lead compounds whose pharmacokinetic parameters warranted investigation.
Methods: Control and Pahenu2−/− 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 AIB in vivo. AIB and MAIB partitioned similarly from sera to the brain and liver, with an approximate 10-fold higher accumulation in the liver compared to the brain. In comparison to MAIB, AIB accumulated to approximately 3 to 7-fold higher concentration in the brain. Analysis of the brain and liver revealed a trend toward decreased Phe with increased MAIB serum concentration.
Conclusions: Our data support further pharmacokinetic characterization of MAIB and AIB in preparation for additional preclinical safety, toxicity and tolerability studies of both AIB and MAIB.
| Reference Key |
vogel2015molecularphysiological
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|---|---|
| Authors | ;Kara R. Vogel;Garrett R. Ainslie;Brian Phillips;Erland Arning;Teodoro Bottiglieri;Danny D. Shen;K. Michael Gibson |
| Journal | advances in skin & wound care |
| Year | 2015 |
| DOI |
10.1016/j.ymgmr.2015.03.009
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