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

Abstract

The effects of a non-ionic surfactant, polysorbate 80, and the sodium salt of the saturated fatty acid, sodium caprate (C10), as potential brain absorption enhancers for vigabatrin were studied. Vigabatrin is an enzyme-activated irreversible inhibitor of gamma-aminobutyric acid (GABA) transaminase that increases brain and cerebrospinal GABA concentrations in animals and man. Before intravenous administration, a range of concentrations of the surfactants were tested using erythrocyte lysis or the red blood cell lysis test to establish the non-toxic concentration range. Vigabatrin was dissolved in 0.1% polysorbate 80 and 0.1% sodium caprate and administered intravenously in doses of 4 mL kg(-1) to male Wistar rats (230-250 g; n = 3). Rats were killed 2 h after drug and surfactant administration and the brains were immediately removed and homogenized in 0.4 M perchloric acid. Selected ion monitoring electrospray mass spectrometry was used to determine the concentration of vigabatrin and GABA directly from the perchloric acid extract of the rat brain. This method was developed to increase the speed and efficiency of the analysis by removing the need for complex extraction and derivatization procedures while retaining the specificity of the mass spectrometer as a detector. The stability of both vigabatrin and GABA in perchloric acid was established by monitoring their pseudo molecular ions in standard solutions at timed intervals over 24 h. Although the detection level for vigabatrin and GABA was at least 50 pg, only GABA was detected in rat brain. Vigabatrin caused a small increase in whole brain GABA. However, GABA levels were 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 the rats is lowered by the presence of vigabatrin in the brain. Vigabatrin alone 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.

Elevated endogenous GABA level correlates with decreased fMRI signals in the rat brain during acute inhibition of GABA transaminase

“…The brain tissue corresponding to the spectroscopy voxel was removed and weighed. Extraction using perchloric acid (PCA) (12%, 3–4 ml/g) was carried out as described previously (Dimitrijevic et al,2001; Patel et al,2001). Brain extracts were centrifuged at 13,000 rpm for 20 min at 4°C.…”

Graded reversible opening of the rat blood–brain barrier by intracarotid infusion of sodium caprate

“…One other BBB study showed that intravenous C10 augments brain uptake of circulating vigabatrin in the rat (Dimitrijevic et al, 2001). By contrast, many papers describe C10 enhancement of substance delivery across the epithelial mucosal lining in lung and gut, e.g., adenoviral gene transfer to lung (Gregory et al, 2003) and gut drug absorption (Lindmark et al, 1997).…”

A new strategy for in vivo spectral editing. Application to GABA editing using selective homonuclear polarization transfer spectroscopy

“…Immediately after in vivo data acquisition, the metabolism of the rat brain was arrested using a microwave fixation system (Model TMW-6402C, Muromachi Kikai, Tokyo, Japan), which inactivates enzymatic processes in approximately one second without affecting the level or the distribution of GABA [24]. Perchloric acid (PCA) extracts of the brain tissue corresponding to the spectroscopy voxel were prepared as described previously [25] and then lyophilized repeatedly. The high-resolution spectra of the PCA extracts in D 2 O were acquired using added 3-(trimethylsilyl) propionic-2,2,3,3-d 4 acid (TSP-d 4 ) as a chemical shift reference standard.…”