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Pharmacokinetic and metabolism studies of valproic acid using gas chromatography mass spectrometry Acheampong, Andrew Adu


Di-(3-²H₃-propyl)acetic acid was synthesized and used in pharmacokinetic and metabolism studies of dipropyl acetic acid (valproic acid). Kinetic equivalence of valproic acid and valproic acid-²Hg₆ was demonstrated in a single dose study in a human volunteer. An isotope effect was observed for w-oxidation but the difference in metabolism of the two isotopic forms was not sufficient to make valproic acid-²Hg₆ biologically nonequivalent. In a multiple dose study, the kinetics of valproic acid-²Hg₆ were determined in the presence of steady state concentrations of valproic acid in the same volunteer. Concentrations of valproic acid and valproic acid-²Hg₆ in serum and saliva were determined by gas chromatography mass spectrometry using selected ion monitoring. Saliva drug levels were measured with good precision down to 0.1 μg/ml. Compared to single dose kinetic data, the total body clearance of valproic acid-²Hg₆ increased by 33% at steady state. This could be explained by an increase in the serum free drug fraction. At steady state, intrinsic clearance was found to decrease. Good correlation was found between concentrations of valproic acid in saliva and serum. Serum and urinary metabolites were characterized as their methyl, trimethylsilyl or tert-butyldimethylsilyl derivatives. The metabolism study was facilitated by using the stable isotope tracer technique. A diunsaturated metabolite was identified in serum and urine. The presence of a molecular ion doublet in the mass spectrum reduces the possible structures for this metabolite. A new metabolite, 2-propyl-4-keto-pentanoic acid, was detected in serum and urine and 2-propylsuccinic acid and 2-propylmalonic acid were characterized as metabolites. The identification of metabolites was also verified using synthesized reference compounds.

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