[KSCI] Korea Science Citation Index Service

http://dx.doi.org/10.4333/KPS.2010.40.3.155

Simultaneous Determination of Valproic Acid and its Toxic Metabolites, 4-ene-VPA and 2,4-diene-VPA in Rat Plasma using a Gas Chromatographic-mass Spectrometric Method

Lee, Min-Sun (Integrated Omics Center, Korea Institute of Science and Technology)
Lee, Young-Joo (College of Pharmacy, Kyung Hee University)
Chung, Bong-Chul (Integrated Omics Center, Korea Institute of Science and Technology)
Jung, Byung-Hwa (Integrated Omics Center, Korea Institute of Science and Technology)

Publication Information

Journal of Pharmaceutical Investigation / v.40, no.3, 2010 , pp. 155-160 More about this Journal

Abstract

A gas chromatographic-mass spectrometric (GC-MS) method was developed for the simultaneous determination of valproic acid (VPA) and its toxic metabolites, 4-ene-VPA and 2,4-diene-VPA in rat plasma. Extraction was performed in weak acidic condition (pH 5.2) to avoid degradation of 4-ene-VPA and 2,4-diene-VPA. The recoveries for 4-ene-VPA and 2,4-diene-VPA were more than 70% and that for VPA was 33-42%. R value for each compounds exceeded 0.998 in calibration curve during all the analysis. Accuracy and precision ranged from 88.3 to 113.2% and from 2.16 to 14.2%, respectively The method was successfully applied to monitor plasma concentrations of VPA, 4-ene-VPA and 2,4-diene-VPA after intravenous administration of VPA at the dose of 100 mg/kg, suggesting that these toxic metabolites may involved in the hepatotoxicity induced by VPA.

Keywords

valproic acid (VPA); 4-ene-VPA; 2,4-diene-VPA; quantitative analysis; GC-MS (gas chromatographic-mass spectrometry); pharmacokinetics;

Citations & Related Records

Reference

1	Leis, H.J., Windischhofer, W., Rechberger, G.N., Fauler, G., 2003. Synthesis of [ $^{18}O$ ] valproic acid and its use as an internal standard for the quantitative measurement by gas chromatographyelectron ionization mass spectrometry, J. Chromatogr. B. 784, 69-75. DOI
2	Loscher, W., Nau, H., Wahnschaffe, U., Hönack , D., Rundfeldt, C., Wittfoht, W., Bojic U., 1993. Effects of valproate and E-2-en-valproate on functional and morphological parameters of rat liver. II. Influence of phenobarbital comedication, Epilepsy Res. 15, 113-131. DOI
3	Murakami, K., Sugimoto, T., Nishida, N., Kobayashi , Y., Kuhara, T., Matsumoto, I., 1992. Abnormal metabolism of carnitine and valproate in a case of acute encephalopathy during chronic valproate therapy, Brain Dev. 14, 178-181. DOI ScienceOn
4	Perucca, E., 2002. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience, CNS Drugs, 16, 695-714. DOI
5	Sugimoto, T., Nishida, N., Yasuhara, A., Ono A., Sakane, Y., Matsumura, T., 1983. Reye-like syndrome associated with valproic acid, Brain Dev. 5, 334-337. DOI ScienceOn
6	Yu, D., Gordon, J.D., Zheng, J., Panesar, S.K., Riggs, K.W., Rurak D.W., Abott, F.S., 1995. Determination of valproic acid and its metabolites using gas chromatography with mass selective detection: application to serum and urine samples from sheep, J. Chromatogr. B. 666, 269-281. DOI
7	Zafrani, E.S., Berthelot, P., 1982. Sodium valproate in the induction of unusual hepatotoxicity, Hepatology. 2, 648-649. DOI
8	Zimmerman, H.J., Ishak, K.G., 1982. Valproate-induced hepatic injury: analyses of 23 fatal cases, Hepatology. 2, 591-597. DOI
9	Bryant, A.E., Dreifuss, F.E., 1996. Valproic acid hepatic fatalities. III. U.S. experience since 1986, Neurology. 46, 465-469. DOI
10	Cheng, H., Liu, Z., Blum, W., Byrd, J.C., Klisovic, R., Grever, M.R., Marcucci, G., Chan, K.K., 2007. Quantification of valproic acid and its metabolite 2-propyl-4-pentenoic acid in human plasma using HPLC-MS/MS, J. Chromatogr. B., 850, 206-212. DOI
11	Fisher, E., Wittfohy, W., Nau, H., 1992. Quantitative determination of valproic acid and 14 metabolites in serum and urine by gas chromatography/mass spectrometry, Biomed. Chromatogr. 6, 24-9. DOI
12	Gerber, N., Dickinson, R.G., Harland, R.K., Lynn, R., Houghton, D. L., Antonias, J. I., Schimschock, J.C., 1979. Reye-like syndrome associated with valproic acid therapy, J. Pediatr. 95, 142-144. DOI
13	Kassahun, K., Farrell, K., Abott, F.S., 1991. Identification and characterization of the glutathione and N-acetylcysteine conjugates of (E)-2-propyl-2,4-pentadienoic acid, a toxic metabolite of valproic acid, in rats and humans, Drug. Metab. Dispos. 525-535.