Physiological competition of brain phenylalanine accretion: Initial pharmacokinetic analyses of aminoisobutyric and methylaminoisobutyric acids in Pahenu2 ?/? mice

摘要

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.