Negative ion chemical ionization gas chromatography/mass spectrometry of valproic acid metabolites.
A negative ion chemical ionization (NICI) gas chromatographic/mass spectrometric method is described for the identification of 15 valproic acid (VPA) metabolites as their pentafluorobenzyl derivatives. Samples analyzed were serum, urine and saliva taken from a volunteer on VPA at steady state and also given selected doses of (2H6)VPA. Metabolite peaks were identified by comparison to synthetic standards. All the metabolites, like the parent drug, produced abundant [M - 181]- ions, except 3-keto VPA, which gave an [M - 181 - CO2]- ion. Using the NICI method, two new VPA metabolites were identified. One of these metabolites was characterized as 4'-keto-2-ene VPA by synthesis, while the second one appeared to be a positional isomer of 4'-keto-2-ene VPA. The sensitivity of the method was also sufficient to detect metabolites of VPA in saliva. The ratio of the levels of (Z)-2-ene VPA to (E)-2-ene VPA was much greater in saliva than in serum, suggesting stereoselective plasma protein binding or transport of these two metabolites. The lower limit of detection for the quantification of VPA in serum or saliva was 2 ng ml-1.
Kassahun
K
K
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Burton
R
R
Abbott
F S
FS
D001711:Biotransformation; D002852:Chromatography, Ion Exchange; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D012463:Saliva / Q000032:analysis; D014635:Valproic Acid / Q000032:analysis* / Q000097:blood / Q000378:metabolism
D014635:Valproic Acid