Increased vigabatrin entry into the brain by polysorbate 80 and sodium caprate

The effects of a non-ionic surfactant, polysorbate 80, and the sodium salt of the saturated fatty acid, sodium caprate (C10), as potential brain absor ption enhancers for vigabatrin were studied. Vigabatrin is an enzyme-activa ted irreversible inhibitor of gamma -aminobutyric acid (GABA) transaminase that increases brain and cerebrospinal GABA concentrations in animals and m an. Before intravenous administration, a range of concentrations of the sur factants were tested using erythrocyte lysis or the red blood cell lysis te st to establish the non-toxic concentration range. Vigabatrin was dissolved in 0.1% polysorbate 80 and 0.1% sodium caprate and administered intravenou sly in doses of 4 mL kg(-1) to male Wistar rats (230-250 g; n = 3). Rats we re killed 2h after drug and surfactant administration and the brains were i mmediately removed and homogenized in 0.4 M perchloric acid. Selected ion m onitoring electrospray mass spectrometry was used to determine the concentr ation of vigabatrin and GABA directly from the perchloric acid extract of t he rat brain. This method was developed to increase the speed and efficienc y of the analysis by removing the need for complex extraction and derivatiz ation procedures while retaining the specificity of the mass spectrometer a s a detector. The stability of both vigabatrin and GABA in perchloric acid was established by monitoring their pseudo molecular ions in standard solut ions at timed intervals over 24 h. Although the detection level for vigabat rin and GABA was at least 50 pg, only GABA was detected in rat brain. Vigab atrin caused a small increase in whole brain GABA. However, GABA levels wer e higher in the samples with vigabatrin+enhancer than in the samples where vigabatrin alone was administered. One-way analysis of variance indicated a significant effect of the surfactants on GABA levels (F (5,17) = 11.86, P < 0.01) and vigabatrin absorption was presumed. The rectal temperature of t he rats is towered by the presence of vigabatrin in the brain. Vigabatrin a lone decreased rectal temperature by 6%. When given with either polysorbate 80 or sodium caprate, the extent of temperature lowering was significantly greater (P < 0.001). There was no significant difference after 2 h between polysorbate 80+vigabatrin, and sodium caprate+vigabatrin.