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.
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.
Objective
Initial studies on the use of non-physiological amino acids (NPAAs) to block the accretion of Phe in the brain Pahenu2-/- mice revealed that 2-aminoisobutyrate (AIB) and N-methyl-2-aminoisobutyrate (MAIB) were promising lead compounds whose pharmacokinetic parameters warranted investigation.
Results
MAIB was partially converted to AIB in 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.