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 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.
Centre for Drug Delivery Research, The School of Pharmacy, University of London, UK.
D
D
Dimitrijevic
P S
PS
Whitton
M
M
Domin
K
K
Welham
A T
AT
Florence
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D003652:Decanoic Acids; D004912:Erythrocytes / Q000187:drug effects; D005079:Excipients; D008297:Male; D011136:Polysorbates; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization; D020888:Vigabatrin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D003652:Decanoic Acids; D005079:Excipients; D011136:Polysorbates; C031071:decanoic acid; D005680:gamma-Aminobutyric Acid; D020888:Vigabatrin