Summary
The pharmacokinetics of valproic acid (VPA) have been studied in 6 healthy subjects following a single 600 mg dose, and after multiple doses over 12 days (1200 mg daily) of enteric-coated sodium valproate. A time lag before absorption of 1 to 2 h was observed in each subject, and then absorption was rapid, peak concentrations being recorded 3 to 4 h after administration of the dose. The plasma level decline was biphasic with a terminal half-life of 15.9±2.6 h in the single dose and 17.3±3.0 h in the multiple dose experiments. There was no evidence of dose dependent kinetics or autoinduction. Total plasma clearance was 0.0064±0.0011 l/kg×h. The apparent volume of distribution was small at 0.15±0.2 l/kg. The mean steady state plasma concentration (Css) reached after 4 days was 81.3±13.0 µg/ml. Css observed was lower than Css predicted (99.2±14.7 µg/ml) from single dose kinetics (p<0.001). The difference was probably due to a reduction in plasma protein binding at higher concentrations. VPA concentration in saliva was between 0.4 and 4.5% of the total plasma concentration and was not equal to the concentration of unbound drug in plasma (6.7±0.8% unbound). 3.2% of the dose was excreted in urine as the parent drug and 21.2% as conjugated metabolites.
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References
Arnold, K., Gerber, N.: The rate of decline of diphenylhydantoin in human plasma. Clin. Pharmacol. Ther.11, 121–134 (1970)
Bergamini, L., Mutani, R., Furlan, P.M., Riccio, A.: Le Dépakine dans le traitement de l'épilepsie essentielle ou idiopathique. Arch. Suisse Neurol. Neurochir. Psychiat.106, 1–7 (1970)
Bochner, F., Hooper, W.D., Sutherland, J.M., Eadie, M.I., Tyrer, J.H.: Diphenylhydantoin concentrations in saliva. Arch. Neurol. (Chic.)31, 57–59 (1974)
Burton, B.S.: On the propyl derivatives and decomposition products of ethyl acetoacetate. Amer. chem. J.3, 385–395 (1881)
Eichelbaum, M., Ekbom, K., Ringberger, V.A., Bertilsson L., Rane, A.: Plasma kinetics of carbamazepine and its epoxide metabolite in man during single and multiple dosing. Europ. J. Clin. Pharmacol.8, 337–341 (1975)
Ferrandez, B., Eymard, P.: Méthode rapide d'analyse quantitative du dipropylacétate de sodium dans le sérum ou le plasma. Ann. Pharm. Fr.31, 279–282 (1973)
Gugler, R., Shoeman, D.W., Huffman, D.H., Cohlmia, J.B., Azarnoff, D.L.: Pharmacokinetics of drugs in patients with the nephrotic syndrome. J. clin. Invest.55, 1182–1189 (1975)
Gugler, R., Mueller, G.: Plasma protein binding of valproic acid in healthy subjects and in patients with renal disease. Brit. J. clin. Pharmacol., in press
Hartlapp, J.H., Gugler, R.: Single versus multiple dose pharmacokinetics of clofibrate. Naunyn Schmiedeberg's Arch. Pharmacol.293 Suppl., R 63 (1976)
Jensen, C.J., Gugler, R.: A sensitive GLC method for determination of valproic acid in biological fluids. J. Chromatogr.137, 188–193 (1977)
Klotz, U., Antonin, K.H.: Pharmacokinetics and bioavailability sodium valproate. Clin. Pharmacol. Ther.21, 736–743 (1977)
Loiseau, P., Brachet, A. and Henry, P.: Concentration of dipropylacetate in plasma. Epilepsia16, 609–615 (1975)
Matin, S.B., Wan, S.H., Karam, J.H.: Pharmacokinetics of tolbutamide: Prediction by concentration in saliva. Clin. Pharmacol. Ther.16, 1052–1058 (1974)
Meinardi, H.: Clinical trials of antiepileptic drugs. Psychiat. Neurol. Neurochir.74, 435–483 (1971)
Meunier, H., Carraz, G., Meunier, V., Eymard, M.: Propriétés pharmacodynamiques de l'acide n-propylacétique. Thérapie18, 435–438 (1963)
Reidenberg, M.M., Odar-Cederlöf, I., von Bahr, C., Borgå, O., Sjöqvist, F.: Protein binding of diphenylhydantoin and desmethylimipramine in plasma from patients with poor renal function. N. Engl. J. Med.285, 264–267 (1971)
Remmer, H., Siegert, M.: Kumulation und Elimination von Phenobarbital. Naunyn Schmiedeberg's Arch. Pharmakol.243, 479–494 (1962)
Richens, A., Ahmad, S.: Controlled trial of sodium valproite in severe epilepsy. Brit. med. J.4, 255–256 (1975)
Simon, D., Penry, J.K.: Sodium di-n-propylacetate (DPA) in the treatment of epilepsy. Epilepsia16, 549–573 (1975)
Sonnen, A.E.H., Blom, G.F., Meijer, J.W.A.: Enteric coated dipropylacetate (Depakine). Clinical Pharmacology of Antiepileptic Drugs. (ed. Schneider, H., Janz, D., Gardner-Thorpe, C., Meinardi, H., Sherwin, A.L., pp. 229–234. Berlin, Heidelberg, New York: Springer-Verlag 1975
Suzuki, M., Marujama, H., Ishibashi, Y., Ogawa, S., Seki, T., Hoshino, M., Maekawa, K., Yo, T., Sato, Y.: Double blind comparative trial of sodium dipropylacetate and ethosuximide in epilepsy in children. The special emphasis on pure petit mal seizure. (Japan.) Med. Prog.82, 470–488 (1972)
Troupin, A. S., Friel, P.: Anticonvulsant level in saliva, serum and cerebrospinal fluid. Epilepsia16, 223–227 (1975)
Wagner, J.G., Northam, J.I., Alway, C.D., Carpenter, O.S.: Blood levels of drugs at equilibrium state after multiple dosing. Nature207, 1301–1302 (1965)
Wallace, S., Brodie, M.J.: Decreased drug binding in patients with chronic hepatic disease. Europ. J. Clin. Pharmacol.9, 429–432 (1976)
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Gugler, R., Schell, A., Eichelbaum, M. et al. Disposition of valproic acid in man. Eur J Clin Pharmacol 12, 125–132 (1977). https://doi.org/10.1007/BF00645133
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DOI: https://doi.org/10.1007/BF00645133