Clinical Pharmacokinetics of Valproic Acid — 1988

Springer Science and Business Media LLC - Tập 15 - Trang 367-389 - 2012
Gaetano Zaccara1,2, Andrea Messori1,2, Flavio Moroni1,2
1Department of Neurology, University of Florence, Pharmaceutical Service, Careggi Hospital, Florence, Italy
2Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy

Tóm tắt

Sodium valproate (valproic acid) has been widely used in the last decade and is now considered a relatively safe and effective anticonvulsant agent. Recently, several investigators have proposed its use in the treatment of anxiety, alcoholism and mood disorders, although these indications require further clinical studies. Valproic acid is available in different oral formulations such as solutions, tablets, enteric-coated capsules and slow-release preparations. For most of these formulations bioavailability approaches 100%, while the absorption half-life varies from less than 30 minutes to 3 or 4 hours depending on the type of preparation used. Once absorbed, valproic acid is largely bound to plasma proteins and has a relatively small volume of distribution (0.1 to 0.4 L/kg). Its concentration in CSF is approximately one-tenth that in plasma and is directly correlated with the concentration found in tears. At therapeutic doses, valproic acid half-life varies from 10 to 20 hours in adults, while it is significantly shorter (6 to 9 hours) in children. Valproic acid undergoes extensive liver metabolism. Numerous metabolites have been positively identified and there is reasonable evidence that several of them contribute to its pharmacological and toxic actions. In fact, several valproic acid metabolites have anti-convulsant properties, while many of the side effects it may cause (e.g. those related to hyperammonaemia or liver damage) are most often observed in patients previously treated with phenobarbitone. This could indicate that induction of liver enzymes is responsible for the formation of toxic valproic acid metabolites.

Tài liệu tham khảo

Abbott FS, Kassam J, Orr JM, Farrell K. The effect of aspirin on valproic acid metabolism. Clinical Pharmacology and Therapeutics 40: 94–100, 1986 Acheampong A, Abbott F, Burton R. Identification of valproic acid metabolites in human serum and urine using hexadeuterated valproic acid and gas Chromatographic mass spectrometric analysis. Biomedical Mass Spectrometry 10: 586–595, 1983 Albani F, Riva R, Procaccianti G, Baruzzi A, Perucca E. Free fraction of valproic acid: in vitro time-dependent increase and correlation with free fatty acid concentration in human plasma and serum. Epilepsia 24: 65–73, 1983 Albright PS, Bruni J, Suria D. Pharmacokinetics of enteric-coated valproic acid. Therapeutic Drug Monitoring 6: 21–23, 1984 Armijo JA, Herranz JL, Arteaga R, Valiente R. Poor correlation between single-dose data and steady-state kinetics for phenobarbitone, primidone, carbamazepine and sodium valproate in children during monotherapy. Clinical Pharmacokinetics 11: 323–335, 1986 Ater SB, Swinyard EA, Tolman KG, Madsen JA, Matsuo F. Effects of SKF525A, phenobarbital, and carnitine on the anticonvulsant activity and neurotoxicity of valproate in mice. Epilepsia 25: 599–604, 1984 Atkinson HC, Begg EJ, Darlow BA. Drugs in human milk — clinical pharmacokinetic considerations. Clinical Pharmacokinetics 14: 217–240, 1988 Barré J, Chamouard JM, Houin J, Tillement JP. Equilibrium dialysis, ultrafiltration, and ultracentrifugation compared for determining the plasma protein binding characteristics of valproic acid. Clinical Chemistry 31: 60–64, 1985 Barré J, Didey F, Delion F, Tillement JP. Problems in therapeutic drug monitoring: free level drug monitoring. Therapeutic Drug Monitoring 10: 133–143, 1988 Bauer LA, Davis R, Wilensky A, Raisys VA, Levy RH. Diurnal variation in valproic acid clearance. Clinical Pharmacology and Therapeutics 35: 505–509, 1984 Bauer LA, Davis R, Wilensky A, Raisys VA, Levy RH. Valproic acid clearance: unbound fraction and diurnal variations in young and elderly adults. Clinical Pharmacology and Therapeutics 37: 697–700, 1985 Bauer LA, Harris C, Wilensky AJ, Raisys VA, Levy RH. Ethosuximide kinetics: possible interaction with valproic acid. Clinical Pharmacology and Therapeutics 31: 741–745, 1982 Becker CM, Harris RA. Influence of valproic acid on hepatic carbohydrate and lipid metabolism. Archives of Biochemistry 223: 381–392, 1983 Benedetti MA, Rumigny JF, Dostert P. Mécanismes d’action et toxicologie biochimique de l’acide valproique. L’Encephale 10: 177–188, 1984 Benet LZ, Sheiner LB. Design and optimization of dosage regimens: pharmacokinetic data. In Goodman Gilman A et al. (Eds) The pharmacological basis of therapeutics, pp. 1663–1733, MacMillan, New York, 1985 Bialer M, Friedman M, Dubrovsky J. Pharmacokinetic evaluation of novel sustained-release dosage forms of valproic acid in humans. Biopharmaceutics and Drug Disposition 6: 401–411, 1985a Bialer M, Friedman M, Dubrovsky J. Relation between absorption half-life values of four novel sustained-release dosage forms of valproic acid in dogs and humans. Biopharmaceutics and Drug Disposition 7: 495–500, 1986 Bialer M, Hussein Z, Raz I, Abramsky O, Herishanu Y, et al. Pharmacokinetics of valproic acid in volunteers after a single dose study. Biopharmaceutics and Drug Disposition 6: 33–42, 1985b Bialer M, Rubinstein A, Raz I, Abramsky O. Pharmacokinetics of valpromide after oral administration of a solution and a tablet to healthy volunteers. European Journal of Clinical Pharmacology 27: 501–503, 1984 Bourgeois BFD. Pharmacological interactions between valproate and other drugs. American Journal of Medicine 84: 29–33, 1988 Brown JE, Kitchell BB, Bjornsson TD, Shand DG. The artifactual nature of heparin-induced drug protein binding alterations. Clinical Pharmacology and Therapeutics 30: 636, 1981 Bruno J, Gallo JM, Lee CS, Perchalski RJ, Wilder BJ. Interaction of valproic acid with phenytoin. Neurology 30: 1233–1236, 1980 Campostrini R, Zaccara G, Rossi L, Paganini M, Dorigotti A, et al. Valproate-induced hyperammonemia in two epileptic identical twins. Journal of Neurology 232: 167–168, 1985 Chadwick DW. Concentration effect relationships of valproic acid. Clinical Pharmacokinetics 10: 155–163, 1985 Chapman A, Keane PE, Meldrum BS, Simiand J, Vernieres JC. Mechanism of anticonvulsant action of valproate. Progress of Neurobiology 19: 315–359, 1982 Chiba K, Suganuma T, Ishizaki T, Iriki T, Shirai Y, et al. Comparison of steady-state pharmacokinetics of valproic acid in children between monotherapy and multiple antiepileptic treatment. Journal of Pediatrics 106: 653–658, 1985 Cloyd JC, Kriel RL. Bioavailability of rectally administered valproic acid syrup. Neurology 31: 1348–1352, 1981 Coulter DL. Carnitine deficiency: a possible mechanism for valproate hepatotoxicity. Lancet 1: 689, 1984 Coulter D, Allen RJ. Secondary hyperammonaemia: a possible mechanism for valproate encephalopathy. Lancet 1: 1310–1311, 1980 Coulter DL, Allen RJ. Hyperammonemia with valproic acid therapy. Journal of Pediatrics 99: 317–319, 1981 Cramer JA, Mattson RH, Benett BM, Swick CT. Variable free and total valproic acid concentration in sole and multi-drug therapy. In Levy RH et al. (Eds) Metabolism of antiepileptic drugs, Raven Press, New York, 1984 D’Arcy PK. Oral contraceptives in epilepsy. Pharmacy International 7: 268–269, 1986 De Vivo DC. Reye syndrome. A metabolic response to an acute mitochondrial insult? Neurology 28: 105–108, 1978 Dreifuss FE, Santilli N. Valproic acid hepatic fatalities: analysis of United States cases. Neurology 36: 175–178, 1986 Eadie MJ, Hooper WD, Dickinson RG. Valproate-associated hepatotoxicity and its biochemical mechanisms. Medical Toxicology 3: 85–106, 1988 Eichelbaum M. Pharmacokinetic drug interactions. Journal of Clinical Pharmacology 26: 469–473, 1986 Emrich HM, Dose M, von Zerssen D. The use of sodium valproate, carbamazepine and oxcarbamazepine in patients with affective disorders. Journal of Affective Disorders 8: 243–250, 1985 Emrich HM, von Zerssen D, Kissling W, Moller HJ. Therapeutic effect of valproate in mania. American Journal of Psychiatry 138: 256–260, 1981 Ferrandez B, Eymard P. Metabolism of valproate sodium in rabbit, rat, dog, and man. Epilepsia 18: 169–182, 1977 Frey HH, Löscher W. Distribution of valproate across the interface between blood and cerebrospinal fluid. Neuropharmacology 17: 637–642, 1978 Froscher W, Burr W, Penin H, Wol J, Wulau P, et al. Free level monitoring of carbamazepine and valproic acid: clinical significance. Clinical Neuropharmacology 8: 362–371, 1985 Furlanut M, Schiaulini P, Rizzoni G. Possible enzymatic inhibition by valproate. International Journal of Clinical Pharmacology Research 11: 269–272, 1982 Gastaut H, Noel P. A case of fatal toxic hepatitis: recommendations for the administration of sodium valproate. Epilepsia 22: 711–713, 1981 Gerber N, Dickinson RG, Harland RC, Lynn RK, Houghton D, et al. Reye-like syndrome associated with valproic acid therapy. Journal of Pediatrics 95: 142–144, 1979 Glasgow AM, Chase HP. Production of the features of Reye’s syndrome in rats with 4-pentenoic acid. Pediatric Research 9: 133–138, 1975 Gram L, Flachs H, Wurtz-Jorgensen A, Parnas J, Andersen B. Sodium valproate: serum level and clinical effect in epilepsy. A controlled study. Epilepsia 20: 303–312, 1979 Granneman GR, Wang SI, Kesterson JW, Machinist JM. The hepatotoxicity of valproic acid and its metabolites in rats, II: intermediary and valproic acid metabolism. Hepatology 4: 1153–1158, 1984a Granneman GR, Wang SI, Machinist JM, Kesterson JW. Aspects of the metabolism of valproic acid. Xenobiotica 14: 375–387, 1984b Gugler R, Schell A, Eichelbaum M, Froscher W, Schulz HU. Disposition of valproic acid in man. European Journal of Clinical Pharmacology 12: 125–132, 1977 Gugler R, von Unruh GE. Clinical pharmacokinetics of valproic acid. Clinical Pharmacokinetics 5: 67–83, 1980 Guyot M, Loiseau P, Brachet-Lermain A, Levy RH, Morselli PL. The distribution of valproic acid between serum and cerebrospinal fluid. In Akimoto et al. (Eds) Advances in Epileptology, pp. 293–295, Raven Press, New York, 1982 Haidukewych D, John G, Zielinksy JJ, Rodin RA. Chronic valproic acid therapy and incidence of increases in venous plasma ammonia. Therapeutic Drug Monitoring 7: 290–294, 1985 Haidukewych D, Rodin EA. Monitoring of free valproic acid in epilepsy patients medicated with co-anticonvulsants. Therapeutic Drug Monitoring 4: 209–212, 1982 Hall K, Otten N, Johnston B, Irvine-Meek J, Leroux M, et al. A multivariable analysis of factors governing the steady-state pharmacokinetics of valproic acid in 52 young epileptics. Journal of Clinical Pharmacology 25: 261–268, 1985 Harding GF, Herrick CE, Jeavons PM. A controlled study of the effect of sodium valproate on photosensitive epilepsy and its prognosis. Epilepsia 19: 555–565, 1978 Heinemeyer G, Nau H, Hildebrandt AG, Roots I. Oxidation and glucuronidation of valproic acid in male rats — influence of phenobarbital, 3-methylcholanthrene, beta-naphthoflavone and clofibrate. Biochemical Pharmacology 34: 133–139, 1985 Henriksen O, Johannessen SI. Clinical and pharmacokinetic observations on sodium valproate — a five year follow up study in 100 children with epilepsy. Acta Neurologica Scandinavica 65: 504–523, 1982 Hillman RE, Berg L, DeVivo D. Valproic acid (dipropylacetic acid) — an inhibitor of branched chain fatty acid dehydrogenase. Pediatric Research 12: 507, 1978 Ishizaki T, Chiba K, Saito M. The effects of neuroleptics (haloperidol and chlorpromazine) on pharmacokinetic of valproic acid in schizophrenic patients. Journal of Clinical Psycho-pharmacology 4/5: 254–261, 1984 Jakobs C, Löscher W. Identification of metabolites of valproic acid in serum of humans. Epilepsia 19: 591–602, 1978 Jeavons PM. Non dose-related effects of valproate. Epilepsia 25 (Suppl. 1): 50–55, 1984 Jeavons PM, Clark JE. Sodium valproate in treatment of epilepsy. British Medical Journal 2: 584–586, 1974 Kapetanovic IM, Kupferberg HJ, Porter RJ. Mechanism of valproate-phenobarbital interaction in epileptic patients. Clinical Pharmacology and Therapeutics 29: 480–486, 1981 Keene DL, Humphreys P, Carpenter B, Fletcher JP. Valproic acid producing a Reye-like syndrome. Journal Canadien des Sciences Neurologiques 6: 435–437, 1982 Kesterson JW, Granneman GR, Machinist JM. The hepatotoxicity of valproic acid and its metabolites in rats, I: toxicologic, biochemical and histopathologic studies. Hepatology 4: 1143–1152, 1984 Klotz U, Antonin KH. Pharmacokinetics and bioavailability of sodium valproate. Clinical Pharmacology and Therapeutics 21: 736–743, 1977 Klotz U, Rapp T, Mueller WA. Disposition of valproic acid in patients with liver disease. European Journal of Clinical Pharmacology 13: 55–60, 1978 Kochen W, Imbeck H, Jackobs C. Untersuchungen über die Ausscheidung von Metaboliten der Valproinsaure im Urin der Ratte und des Menscher. Arzneimittel-Forschung 27: 1090–1093, 1977 Kuhara T, Inoue Y, Matsumoto M, Shinka T, Matsumoto I, et al. Altered metabolic profiles of valproic acid in a patient with Reye’s syndrome. Clinica Chimica Acta 145: 135–142, 1985 Laub MC, Paetzke-Brunner I, Jaeger J. Serum carnitine during valproic acid therapy. Epilepsia 27: 559–562, 1986 Levy RH, Cenraud B, Loiseau P, Akbaraly R, Brachet-Lierman A, et al. Meal-dependent absorption of enteric-coated sodium valproate. Epilepsia 21: 273–280, 1980 Levy RH, Moreland TA, Morselli PL, Guyot M, Brachet Liermain A, et al. Carbamazepine-valproic acid interaction in man and rhesus monkey. Epilepsia 25: 338–345, 1984 Lewis JH, Zimmerman HJ, Garrett CT, Rosenberg E. Valproateinduced hepatic steatogenesis in rats. Hepatology 2: 870–873, 1982 Löscher W. Concentration of metabolites of valproic acid in plasma of epileptic patients. Epilepsia 22: 169–178, 1981 Löscher W, Nau H. Valproic acid: metabolite concentrations in plasma and brain, anticonvulsant activity, and effects on GABA metabolism during subacute treatment in mice. Archives Internationales de Pharmacodynamie et de Thérapie 257: 20–31, 1982 Löscher W, Nau H. Distribution of valproic acid and its metabolites in various brain areas of dogs and rats following acute and prolonged treatment. Journal of Pharmacology and Experimental Therapeutics 226: 845–854, 1983 Löscher W, Nau H. Pharmacological evaluation of various metabolites and analogues of valproic acid: anticonvulsant and toxic potencies in mice. Neuropharmacology 24: 427–435, 1985 Löscher W, Nau H, Marescaux C, Vergnes M. Comparative evaluation of anticonvulsant and toxic potencies of valproic acid and 2-en-valproic acid in different animal models. European Journal of Pharmacology 99: 211–218, 1984 Marescaux C, Bonardi JM, Rumbach L, Warter JM, Juif J, et al. État stuporeux prolongé au cours d’une monothérapie au valproate de sodium immédiatement reversible après injection intraveineuse de diazepam. Revue Neurologique 137: 635–638, 1981 Marescaux C, Warter JM, Laroye M, Rumbach L, Micheletti G, et al. Le valproate de sodium: une drogue hyperammonémiante. Étude chez l’épileptique et chez le volontaire sain. Journal of the Neurological Sciences 58: 195–209, 1983 Marescaux C, Warter JM, Micheletti G, Rumbach L, Coquillat G, et al. Stuporous episodes during treatment with sodium valproate: report of seven cases. Epilepsia 23: 297–305, 1982 Matsumoto I, Kuhara T, Yoshino M. Metabolism of branched medium fatty acid, II: beta-oxidation of sodium dipropylacetate in rats. Biomedical Mass Spectrometry 3: 235–240, 1976 Mattson RH. Valproate interactions with other drugs. In Woodbury et al. (Eds) Antiepileptic Drugs, 2nd ed, pp. 579–589, Raven Press, New York, 1982 Mattson RH, Cramer JA. Valproic acid and ethosuximide interaction. Annals of Neurology 7: 583–584, 1980 Mattson RH, Cramer JA, Williamson PD, Novelly R. Valproic acid in epilepsy: clinical and pharmacological effects. Annals of Neurology 3: 20–25, 1978 May T, Rambeck B. Serum concentration of valproic acid: influence of dose and comedication. Therapeutic Drug Monitoring 7: 387–390, 1985 Meinardi H, Hanke NF, Van Beveren J. Sodium di-n-propylacetate: estimation of effective serum levels. Pharmaceutisch Weekblad 109: 435–438, 1974 Meunier H, Carraz G, Meunier V, Eymard M. Propriétés pharmacodynamiques de l’acide n-propylacétique. Thérapie 18: 435–438, 1963 Mihaly GW, Vajda FJ, Miles JL, Louis WJ. Single and chronic dose pharmacokinetic studies of sodium valproate in epileptic patients. European Journal of Clinical Pharmacology 16: 23–29, 1979 Monaco F, Piredda S, Mutani R, Mastropaolo C, Tondi M. The free fraction of valproic acid in tears, saliva, and cerebrospinal fluid. Epilepsia 23: 23–26, 1982 Moolenar F, Greuing WJ, Huzinga T. Absorption rate and bioavailability of valproic acid and its sodium salt from rectal dosage forms. European Journal of Clinical Pharmacology 17: 309–313, 1980 Mortensen PB, Gregersen N, Kolvraa S, Christensen E. The occurrence of C6-C10-dicarboxylic acids in urine from patients and rats treated with dipropylacetate. Biochemical Medicine 24: 153–161, 1980 Murphy JV, Marquardt K. Asymptomatic hyperammonemia in patients receiving valproic acid. Archives of Neurology 39: 591–592, 1982 Nau H, Löscher W. Valproic acid: brain and plasma levels of the drug and its metabolites, anticonvulsant effects and gammaaminobutyric acid (GABA) in the mouse. Journal of Pharmacology and Experimental Therapeutics 220: 654–659, 1982 Nau H, Löscher W. Valproic acid and metabolites: pharmacological and toxicological studies. Epilepsia 25 (Suppl.): 14–22, 1984 Nau H, Rating D, Koch S, Hauser I, Helge H. Valproic acid and its metabolites: placental transfer via mother’s milk and clinical status in neonates of epileptic mothers. Journal of Pharmacology and Experimental Therapeutics 219: 768–777, 1981 Nitsche V, Mascher H. The pharmacokinetics of valproic acid after oral and parenteral administration in healthy volunteers. Epilepsia 23: 153–162, 1982 Nutt JG, Kupferberg HJ. Linear relationship between plasma concentration and dosage of sodium valproate. Epilepsia 20: 589–592, 1979 Ohtani Y, Endo F, Matuda I. Carnitine deficiency and hyperammonemia associated with valproic acid therapy. Journal of Pediatrics 101: 782–785, 1982 Paganini M, Zaccara G, Moroni F, Campostrini R, Bendoni L, et al. Lack of relationship between sodium valproate-induced adverse effects and the plasma concentration of its metabolite 2-propylpenten-4-oic acid. European Journal of Clinical Pharmacology 32: 219–222, 1987 Patel IH, Levy RH. Valproic acid binding to human serum albumin and determination of free fraction in the presence of anticonvulsants and free fatty acids. Epilepsia 20: 85–90, 1979 Pisani F, Amendola A, Fazio A, Oteri G, Primerano G, et al. Increased dipropylacetic acid bioavailability from dipropylacetamide by food. Epilepsia 23: 115–121, 1982 Pisani F, Di Perri R. Some clinical pharmacological aspects of n-dipropylacetamide. Italian Journal of Neurological Sciences 4: 245–249, 1980 Pisani F, Di Perri R. Intravenous valproate: effects on plasma and saliva phenytoin levels. Neurology 31: 467–470, 1981 Pisani F, Fazio A, Oteri G, Di Perri R. Dipropylacetic acid plasma levels: diurnal fluctuations during chronic treatment with dipropylacetamide. Therapeutic Drug Monitoring 3: 297–301, 1981 Pisani F, Fazio A, Oteri G. Sodium valproate and valpromide: differential interactions with carbamazepine in epileptic patients. Epilepsia 27: 548–552, 1986a Pisani F, Narbone MC, Trunfio C. Valproic acid-ethosuximide interaction: a pharmacokinetic study. Epilepsia 25: 229–233, 1984 Pisani F, Primerano G, D’Agostino AA, Spina E, Fazio A. Valproic acid-amitriptyline interaction in man. Therapeutic Drug Monitoring 8: 382–383, 1986b Pollack GM, McHugh WB, Gengo FM, Ermer JC, Shen DD. Accumulation and washout kinetics of valproic acid and its active metabolites. Journal of Clinical Pharmacology 26: 668–676, 1986 Post RM. Mechanism of action of carbamazepine and related anticonvulsants. In Meltzer HY (Ed.) Psychopharmacology. The third generation of progress, pp. 567–576, Raven Press, New York, 1987 Prickett KS, Baillie TA. Metabolism of valproic acid by hepatic microsomal cytochrome P-450. Biochemical and Biophysical Research Communications 122: 1166–1173, 1984 Pugh CB, Garnett WR, Poynor WI, Pellock JM. Single-dose model for predicting steady-state valproic acid serum concentrations in seizure patients. Clinical Pharmacy 3: 643–649, 1984 Rapeport WG, Mendelow AD, French G. Plasma protein binding and CSF concentrations of valproic acid in man following acute oral dosing. British Journal of Clinical Pharmacology 16: 365–369, 1983 Redenbaugh GE, Sato S, Penry JK, Dreifuss FE, Kupferberg HJ. Sodium valproate: pharmacokinetics and effectiveness in treating intractable seizures. Neurology 30: 1–6, 1980 Rettie AE, Rettenmeier AW, Howald WN, Baillie T. Cytochrome P-450-catalyzed formation of 4-en-VPA, a toxic metabolite of valproic acid. Science 235: 890–893, 1987 Riva R, Albani F, Baruzzi A, Galvani I, Perucca E. Determination of unbound valproic acid concentration in plasma by equilibrium dialysis and gas-liquid chromatography: methodological aspects and observations in epileptic patients. Therapeutic Drug Monitoring 4: 341–352, 1982 Riva R, Albani F, Contin M, Baruzzi A, Altomare M, et al. Mechanism of altered drug binding to serum proteins in pregnant women: studies with valproic acid. Therapeutic Drug Monitoring 6: 25–30, 1984 Riva R, Albani F, Cortelli P, Gobbi G, Perucca E, et al. Diurnal fluctuations in free and total plasma concentrations of valproic acid at steady-state in epileptic patients. Therapeutic Drug Monitoring 5: 191–196, 1983 Rodin EA, De Sousa G, Haidukewych D. Dissociation between free and bound phenytoin levels in presence of valproate sodium. Archives of Neurology 38: 240–242, 1981 Rowan AJ, Binnie CD, Warfield CA, Meinardi H, Mejer JWA. The delayed effect of sodium valproate on the photoconvulsive response in man. Epilepsia 20: 61–68, 1979 Sackellares JC, Lee SI, Dreifuss FE. Stupor following administration of valproic acid to patients receiving other antiepileptic drugs. Epilepsia 20: 697–703, 1979 Sackellares JC, Sato S, Dreifuss FE, Penry JK. Reduction of steady-state valproate levels by other antiepileptic drugs. Epilepsia 22: 437–441, 1981 Schafer H, Luhrs R. Metabolite pattern of valproic acid, part I: gas Chromatographic determination of the valproic acid metabolite artifact, heptanone-3, 4- and 5-hydroxy valproic acid lactone. Arzneimittel-Forschung 28: 622–627, 1978 Schafer H, Luhrs R. On the responsibility of the metabolite pattern for potential side effects in the rat being treated with valproic acid, 2-propylpenten-2-oic acid, and 2-propylpenten-4-oic acid. In Levy RH (Ed.) Metabolism of antiepileptic drugs, pp. 73–83, Raven Press, New York, 1984 Scheffner D. Fatal liver failure in children on valproate. Lancet 2: 511, 1986 Schmid RD. Propionic acid and dipropylacetic acid in the urine of patients treated with dipropylacetic acid. Clinica Chimica Acta 74: 39–42, 1977 Schobben F, Vree TB, van der Klein E, Ciaessens R, Reiner WO. Metabolism of valproic acid in monkey and man. In Johannessen et al. (Eds) Antiepileptic therapy: advances in drug monitoring, pp. 91–102, Raven Press, New York, 1980 Slattery JT, Gibaldi M, Koup JR. Prediction of maintenance dose required to attain a desired drug concentration at steady-state from a single determination of concentration after an initial dose. Clinical Pharmacokinetics 5: 337–385, 1980 Snead OC, Miles MV. Treatment of status epilepticus in children with rectal sodium valproate. Journal of Pediatrics 106: 323–325, 1985 Suchy F, Balistreri W, Buchino J, Sondheimer J, Bates S, et al. Acute hepatic failure associated with the use of sodium valproate. New England Journal of Medicine 300: 962–966, 1979 Svensson CK, Woodruff MN, Baxter JG, Lalka D. Free drug concentration monitoring in clinical practice: rationale and current status. Clinical Pharmacokinetics 11: 450–469, 1986 Thorpy MJ. Rectal valproate syrup and status epilepticus. Neurology 28: 897–901, 1980 Thurston JH, Carroll JE, Dodson WE, Hauhart RE, Tasch V. Chronic valproate administration reduces fasting ketonemia in children. Neurology 33: 1348–1350, 1983 Thurston JH, Carroll JE, Hauhart RE, Schiro JA. A single therapeutic dose of valproate affects liver carbohydrate, fat, adenylate, amino acid, coenzyme A, and carnitine metabolism in infant mice: possible clinical significance. Life Sciences 36: 1643–1651, 1985 Turnbull DM, Bone AJ, Bartlett K, Koundakjian PP, Sherratt HS. The effects of valproate on intermediary metabolism in isolated rat hepatocytes and intact rats. Biochemical Pharmacology 32: 1887–1892, 1983a Turnbull TM, Rawlins MD, Weightman D, Chadwick DW. Plasma concentrations of sodium valproate: their clinical value. Annals of Neurology 14: 38–42, 1983b Vajda FJ, Donnan GA, Phillips J, Bladin PF. Human brain, plasma and cerebrospinal fluid concentration of sodium valproate after 72 hours of therapy. Neurology 31: 486–487, 1981 Vajda FJ, Mihaly GW, Miles JL, Donnan JA, Bladin PF. Rectal administration of sodium valproate in status epilepticus. Neurology 28: 897–899, 1978 Vajda FJ, Symington GR, Bladin PF. Rectal valproate in intractable status epilepticus. Lancet 1: 359–360, 1977 Vayer P, Cash CD, Maitre M. Is the anticonvulsant mechanism of valproate linked to its interaction with the cerebral gammahydroxybutyrate system? TIPS 9: 127–129, 1988 Ware S, Millward-Sadler GH. Acute liver disease associated with sodium valproate. Lancet 22: 1110–1113, 1980 Warter JM, Marescaux C, Brandt C, Rumbach L, Micheletti G, et al. Sodium valproate associated with phenobarbital: effects on ammonia metabolism in humans. Epilepsia 24: 628–633, 1983 Windorfer A, Sauer W, Gadeke R. Elevation of diphenylhydantoin and primidone serum concentration by addition of dipropylacetate, a new anticonvulsant drug. Acta Pediatrica Scandinavica 64: 771–772, 1975 Zaccara G, Boncinelli L, Paganini M, Campostrini R, Arnetoli G, et al. Treatment of epileptic patients with valproie acid does not modify plasma and urine short-chain fatty acids. Acta Neurologica Scandinavica 68: 241–247, 1983 Zaccara G, Campostrini R, Paganini M, Messori A, Valenza T, et al. Long-term treatment with sodium valproate: monitoring of venous ammonia concentrations and adverse effects. Therapeutic Drug Monitoring 9: 31–40, 1987 Zaccara G, Campostrini R, Paganini M, Moroni F, Valenza T, et al. Acute changes of blood ammonia concentrations may help to predict valproic acid short-term adverse effects. Neurology 34: 1519–1521, 1984a Zaccara G, Paganini M, Campostrini R, Arnetoli G, Zappoli R. Hyperammonaemia and valproate-induced alterations of the state of consciousness: a report of 8 cases. European Neurology 23: 104–112, 1984b Zaccara G, Paganini M, Campostrini R, Moroni F, Valenza T, et al. Effect of associated antiepileptic treatment on valproateinduced hyperammonaemia. Therapeutic Drug Monitoring 7: 185–190, 1985 Zafrani ES, Berthelot P. Sodium valproate in the induction of unusual hepatotoxicity. Hepatology 2: 648–649, 1982 Zimmerman CL, Patelud IH, Levy RH, Edwards D, Nelson SD, et al. Protein binding of valproic acid in the presence of elevated free fatty acids in patient and normal human serum. Epilepsia 22: 11–17, 1981 Zimmerman HJ, Ishak KG. Valproate-induced hepatic injury: analyses of 23 fatal cases. Hepatology 2: 591–597, 1982