Summary
Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes.
Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucurono-syltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes.
Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochondrial β-oxidation, whereas it is a weak inducer of other enzyme systems.
Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism.
Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes.
Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required.
Similar content being viewed by others
References
Sander JWAS. Some aspects of prognosis in the epilepsies: a review. Epilepsia 1993; 34: 1007–16
Cascino GD. Epilepsy: contemporary perspectives on evaluation and treatment. Mayo Clin Proc 1994; 69: 1199–211
Beghi E, Perucca E. The management of epilepsy in the 1990s. Drugs 1995; 49: 680–94
Mitchell WG. Long-term prognosis for children with epilepsy. Curr Probl Pediatr 1995; 25: 113–20
Brodie MJ, Dichter MA. Antiepileptic drugs. N Engl J Med 1996; 334: 168–75
Perucca E, Richens A. General principles: biotransformation. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 31–50
Kutt H. Phenytoin: interactions with other drugs: clinical aspects. In: Levy RH, Mattson RH, Meldrum BS, editors. Anti-epileptic drugs. New York: Raven Press, 1995: 315–28
Kutt H. Phenobarbital: interactions with other drugs. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 389–99
Levy RH, Wurden CJ. Carbamazepine: interactions with other drugs. In: Levy RH, Mattson RH, Meldrum BS, editors. Anti-epileptic drugs. New York: Raven Press, 1995: 543–54
Fincham RW, Schottelius DD. Primidone: interactions with other drugs. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 467–75
Scheyer RD, Mattson RH. Valproic acid: interactions with other drugs. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 621–31
Bialer M, Xiaodong S, Perucca E. Ethosuximide: absorption, distribution, and excretion. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 659–65
Klosterskov Jensen P, Saano V, Haring P, et al. Possible interaction between oxcarbazepine and an oral contraceptive. Epilepsia 1992; 33: 1149–52
Baruzzi A, Albani F, Riva R. Oxcarbazepine: pharmacokinetic interactions and their clinical relevance. Epilepsia 1994; 35 Suppl. 3: 14–9
Rambeck B, Wolf P. Lamotrigine clinical pharmacokinetics. Clin Pharmacokinet 1993; 25: 433–43
Reidenberg P, Glue P, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of phenobarbital. Clin Pharmacol Ther 1995; 58: 279–87
Banfield CR, Levy RH. Felbamate: interactions with other drugs. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 813–6
Ben-Menachem E. Vigabatrin: chemistry, absorption, distribution, and elimination. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995:915–23
McLean MJ. Gabapentin: chemistry, absorption, distribution and excretion. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 843–9
Doose DR, Gisclon LG, Liao S, et al. Pharmacokinetics of topiramate. Adv AED Ther 1995; 1: 7–16
Ben-Menachem E. Potential antiepileptic drugs: topiramate. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 1063–70
Perucca E, Bialer M. The clinical pharmacokinetics of the newer antiepileptic drugs: focus on topiramate, zonisamide and tiagabine. Clin Pharmacokinet 1996; 31: 29–46
Bourgeois BF. Drug interaction profile of topiramate. Epilepsia 1996; 37 Suppl. 2: 14–7
Peters DH, Sorkin EM. Zonisamide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy. Drugs 1993; 45: 760–87
Nakasa H, Komiya M, Ohmori S, et al. Characterization of human liver microsomal cytochrome P450 involved in the reductive metabolism of zonisamide. Mol Pharmacol 1993; 44: 216–21
Ostergaard LH, Gram L, Dam M. Potential antiepileptic drugs: tiagabine. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 1057–61
Mengel H, Jansen JA, Sommerville K, et al. Tiagabine: evaluation of the risk of interaction with theophylline, warfarin, digoxin, cimetidine, oral contraceptives, triazolam or ethanol [abstract]. Epilepsia 1995; 36 Suppl. 3: S160
Vesell ES. Genetic and environmental factors affecting drug interactions in man. In: Grahame-Smith DG, editor. Drug interactions. Baltimore: University Park Press, 1977: 119–43
Veronese ME, Doecke CJ, Mackenzie PI, et al. Site-directed mutation studies of human liver cytochrome P450 isoenzymes in the CYP2C subfamily. Biochem J 1993; 289: 533–8
Levy RH, Bajpai M. Phenytoin: interactions with other drugs: mechanistic aspects. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 329–38
Anderson GD, Levy RH. Phenobarbital: chemistry and bio-transformation. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 371–7
Dodson WE, Rust RSJ. Phenobarbital: absorption, distribution, and excretion. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 379–87
Faigle JW, Feldman KF. Carbamazepine: chemistry and bio-transformation. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 499–513
Morselli PL. Carbamazepine: absorption, distribution and excretion. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 515–28
Baillie TA, Sheffels PR. Valproic acid: chemistry and biotransformation. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 589–604
Levy RH, Shen DD. Valproic acid: absorption, distribution, and excretion. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 605–19
Pisani F, Bialer M. Ethosuximide: chemistry and biotransformation. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 655–8
Faigle JW, Menge GP. Metabolic characteristics of oxcarbazepine (Trileptal) and their beneficial implications for enzyme induction and drug interactions. Behav Neurol 1990; 3 Suppl. 1: 21–30
Dam M, Ostergaard LH. Other antiepileptic drugs: oxcarbazepine. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 987–95
Kucharczyk N. Felbamate: chemistry and biotransformation. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 799–806
Perhach JL, Shumaker RC. Felbamate: absorption, distribution and excretion. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 807–12
Bopp BA, Gustavson LE, Johnson MK, et al. Disposition and metabolism of orally administered 14C-tiagabine in humans [abstract]. Epilepsia 1992; 33: 83
So EL, Wolff D, Graves NM, et al. Pharmacokinetics of tiagabine as add-on therapy in patients taking enzyme-inducing antiepilepsy drugs. Epilepsy Res 1995; 22: 221–6
Richens A, Gustavson LE, McKelvy JF, et al. Pharmacokinetics and safety of single-dose tiagabine HCl in epileptic patients chronically treated with four other antiepileptic drug regimens [abstract]. Epilepsia 1991; 32 Suppl. 3: 12
Gustavson LE, Mengel HB. Pharmacokinetics of tiagabine, a gamma-aminobutyric acid-uptake inhibitor, in healthy subjects after single and multiple doses. Epilepsia 1995; 36: 605–11
Netter KJ. Mechanisms of monooxygenase induction and inhibition. Pharmacol Ther 1987; 33: 1–9
Waxman DJ, Azaroff L. Phenobarbital induction of cytochrome P-450 expression. Biochem J 1992; 281: 577–92
Browne TR, LeDuc B. Phenytoin: chemistry and biotransformation. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 283–300
Treiman DM, Woodbury DM. Phenytoin: absorption, distribution, and excretion. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 301–14
Bourgeois BFD. Primidone: chemistry and biotransformation. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 449–57
Cloyd JC, Leppik IE. Primidone: absorption, distribution, and excretion. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 459–66
Bachmann K, Chu CA, Greear V. In vivo evidence that ethosuximide is a substrate for cytochrome P450IIIA. Pharmacology 1992; 45: 121–8
Feldman KF, Dorhofer G, Faigle JW, et al. Pharmacokinetics and metabolism of GP 47779, the main human metabolite of oxcarbazepine (GP 47680) in animals and healthy volunteers. In: Dam M, Gram L, Penry JK, editors. Advances in epileptology. XIIth Epilepsy International Symposium; Copenhagen; 1980 Sept. New York: Raven Press, 1981: 89–96
Theisohn M, Heimann G. Disposition of the antiepileptic oxcarbazepine and its metabolites in healthy volunteers. Eur J Clin Pharmacol 1982; 22: 545–51
Hooper WD, Franklin ME, Glue P, et al. Effect of felbamate on valproic acid disposition in healthy volunteers: inhibition of beta-oxidation. Epilepsia 1996; 37: 91–7
Swinyard EA, Woodhead JH, Franklin R, et al. The effect of chronic felbamate administration on anticonvulsant activity and hepatic drug-metabolizing enzymes in mice and rats. Epilepsia 1987; 28: 295–300
Levy RH, Bishop F, Streeter AJ, et al. Explanation and prediction of drug interactions with topiramate using a CYP450 inhibition spectrum [abstract]. Epilepsia 1995; 36 Suppl. 4: 47
Schmidt D. Benzodiazepines: diazepam. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 705–24
Sato S, Malow BA. Benzodiazepines: clonazepam. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 725–34
Baruzzi A, Michelucci R, Tassinari CA. Benzodiazepines: nitrazepam. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 735–49
Shorvon SD. Benzodiazepines: clobazam. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 763–77
Patsalos PN, Lascelles PT. In vitro hydroxylation of diphenyl-hydantoin and its inhibition by other commonly used anticonvulsant drugs. Biochem Pharmacol 1977; 266: 1929–33
Kutt H, Haynes J, Verebely K, et al. The effect of phenobarbital on plasma diphenylhydantoin level and metabolism in man and rat liver microsomes. Neurology 1969; 19: 611–6
Morselli PL, Rizzo M, Garattini S. Interaction between phenobarbital and diphenylhydantoin in animals and in epileptic patients. Ann NY Acad Sci 1971; 179: 88–107
Windorfer AJ, Sauer W. Drug interactions during anticonvulsant therapy in childhood: diphenylhydantoin, primidone, phenobarbitone, clonazepam, nitrazepam, carbamazepine and dipropylacetate. Neuropaediatrie 1977; 8: 29–41
Duncan JS, Patsalos PN, Shorvon SD. Effects of discontinuation of phenytoin, carbamazepine, and valproate on concomitant antiepileptic medication. Epilepsia 1991; 32: 101–15
Booker HE, Tormey A, Toussaint J. Concurrent administration of phenobarbital and diphenylhydantoin: lack of interference effect. Neurology 1971; 21: 383–485
Eadie MJ, Lander CM, Hooper WD. Factors influencing plasma phenobarbitone levels in epileptic patients. Br J Clin Pharmacol 1977; 4: 541–7
Browne TR, Szabo GK, Evans JE, et al. Phenobarbital does not alter phenytoin steady-state serum concentration or pharmacokinetics. Neurology 1988; 38: 639–42
Christiansen J, Dam M. Influence of phenobarbital and diphenylhydantoin on plasma carbamazepine levels in patients with epilepsy. Acta Neurol Scand 1973; 49: 543–6
Schneider H. Carbamazepine: the influence of other antiepileptic drugs on its serum level. In: Schneider H, Janz D, Gardner-Thorpe C, et al., editors. Clinical pharmacology of anti-epileptic drugs. Berlin: Springer-Verlag, 1975: 189–96
Johannessen SI, Strandjord RE. The influence of phenobarbitone and phenytoin on carbamazepine serum levels. In: Schneider H, Janz D, Gardner-Thorpe C, et al., editors. Clinical pharmacology of anti-epileptic drugs. Berlin: Springer-Verlag, 1975: 201–5
Korczyn AD, Ben-Zvi A, Kaplanski J, et al. Plasma levels of carbamazepine and metabolites: effect of enzyme inducers. In: Meinardi H, Rowan AJ, editors. Advances in epileptology —1977. Amsterdam: Swets & Zeitlinger, 1978: 278–9
Battino D, Bossi L, Croci D, et al. Carbamazepine plasma levels in children and adults: influence of age, dose, and associated therapy. Ther Drug Monit 1980; 2: 315–22
Perucca E, Richens A. Reversal by phenytoin of carbamazepine-induced water intoxication: a pharmacokinetic interaction. J Neurol Neurosurg Psychiatry 1980; 43: 540–5
McKauge L, Tyrer JH, Eadie MJ. Factors influencing simultaneous concentrations of carbamazepine and its epoxide in plasma. Ther Drug Monit 1981; 3: 63–70
Zielinski JJ, Haidukewych D. Dual effects of carbamazepine-phenytoin interaction. Ther Drug Monit 1987; 9: 21–3
Chapron DJ, LaPierre BA, Abou-Elkair M. Unmasking the significant enzyme-inducing effects of phenytoin on serum carbamazepine concentrations during phenytoin withdrawal. Ann Pharmacother 1993; 27: 708–11
Rane A, Hojer B, Wilson JT. Kinetics of carbamazepine and 10,11-epoxide metabolite in children. Clin Pharmacol Ther 1976; 19: 276–83
Westenberg HGM, Van der Kleijn E, Oei TT, et al. Kinetics of carbamazepine and carbamazepine-epoxide, determined by use of plasma and saliva. Clin Pharmacol Ther 1978; 23: 320–8
Brodie MJ, Forrest G, Rapaport WG. Carbamazepine 10,11-epoxide concentrations in epileptics on carbamazepine alone and in combination with other anticonvulsants. Br J Clin Pharmacol 1983; 16: 747–9
Bourgeois BFD, Wad N. Carbamazepine-10,11-diol steady-state serum levels and renal excretion during carbamazepine therapy in adults and children. Ther Drug Monit 1984; 6: 259–65
Ramsay RE, McManus DQ, Guterman A, et al. Carbamazepine metabolism in humans: effect of concurrent anticonvulsant therapy. Ther Drug Monit 1990; 12: 235–41
Liu H, Delgado MR. Interactions of phenobarbital and phenytoin with carbamazepine and its metabolites’ concentrations, concentration ratios, and level/dose ratios in epileptic children. Epilepsia 1995; 36: 249–54
Hansen JM, Siersback-Nielsen K, Skovsted L. Carbamazepine-induced acceleration of diphenylhydantoin and warfarin metabolism in man. Clin Pharmacol Ther 1971; 12: 539–43
Lai ML, Lin TS, Huang JD. Effect of single-and multiple-dose carbamazepine on the pharmacokinetics of diphenylhydantoin. Eur J Clin Pharmacol 1992; 43: 201–3
Zielinski JJ, Haidukewych D, Leheta BJ. Carbamazepine-phenytoin interaction: elevation of plasma phenytoin concentrations due to carbamazepine comedication. Ther Drug Monit 1985; 7: 51–3
Browne TR, Szabo GK, Evans JE, et al. Carbamazepine increases phenytoin serum concentration and reduces phenytoin clearance. Neurology 1988; 38: 1146–50
Lai ML, Huang JD. Dual effect of valproic acid on the pharmacokinetics of phenytoin. Biopharm Drug Dispos 1993; 14: 365–70
Baruzzi A, Bordo B, Bossi L, et al. Plasma levels of di-n-propylacetate and clonazepam in epileptic patients. Int J Clin Pharmacol Biopharm 1977; 15: 403–8
Perucca E, Gatti G, Frigo GM, et al. Disposition of sodium valproate in epileptic patients. Br J Clin Pharmacol 1978; 5: 495–9
Mihaly GW, Vajda FJ, Miles JL, et al. Single and chronic dose pharmacokinetic studies of sodium valproate in epileptic patients. Eur J Pharmacol 1979; 16: 23–9
Johannessen SI, Henriksen O. Pharmacokinetic observations of sodium valproate in healthy subjects and in patients with epilepsy. In: Johannessen SI, Morselli PL, Pippenger CE, et al., editors. Antiepileptic therapy: advances in drug monitoring. New York: Raven Press, 1980: 131–40
Reunanen MI, Luoma P, Myllyla VV, et al. Low serum valproic acid concentrations in epileptic patients on combination therapy. Curr Ther Res 1980; 28: 456–62
Sackellares JC, Sato S, Dreifuss FE, et al. Reduction of steady-state valproate levels by other antiepileptic drugs. Epilepsia 1981; 22: 437–41
May T, Rambeck B. Serum concentrations of valproic acid: influence of dose and co-medication. Ther Drug Monit 1985; 7: 387–90
Cramer JA, Mattson RH, Bennett DM, et al. Variable free and total valproic acid concentrations in sole and multidrug therapy. Ther Drug Monit 1986; 8: 411–6
Kondo T, Otani K, Hirano T, et al. The effects of phenytoin and carbamazepine on serum concentrations of mono-unsaturated metabolites of valproic acid. Br J Clin Pharmacol 1990; 29: 116–9
Perucca E, Hebdige S, Frigo GM, et al. Interaction between phenytoin and valproic acid: plasma protein binding and metabolic effects. Clin Pharmacol Ther 1980; 28: 779–89
Monks A, Boobis S, Wadsworth J, et al. Plasma protein binding interaction between phenytoin and valproic acid in vitro. Br J Clin Pharmacol 1978; 6: 487–92
Monks A, Richens A. Effect of single doses of sodium valproate on serum phenytoin levels and protein binding in epileptic patients. Clin Pharmacol Ther 1980; 27: 89–95
Riva R, Albani F, Contin M, et al. Time-dependent interaction between phenytoin and valproic acid. Neurology 1985; 35: 510–5
Nation RL, Evans AM, Milne RW. Pharmacokinetic interactions with phenytoin. Clin Pharmacokinet 1990; 18: 37–60
May T, Rambeck B. Fluctuations of unbound and total phenytoin concentrations during the day in epileptic patients on valproic acid comedication. Ther Drug Monit 1990; 12: 124–8
Bruni J, Gallo JM, Lee CS, et al. Interactions of valproic acid with phenytoin. Neurology 1980; 30: 1233–6
Wilder BJ, Willmore LJ, Bruni J, et al. Valproic acid: interaction with other anticonvulsant drugs. Neurology 1978; 28: 892–6
Rodin EA, De Sousa G, Haidukewych D, et al. Dissociation between free and bound phenytoin levels in presence of valproate sodium. Arch Neurol 1981; 38: 240–2
Lehtovaara R, Bardy A, Hari R, et al. Sodium valproate and clonazepam interaction with phenytoin and carbamazepine. In: Meinardi H, Rowan AJ, editors. Advances in epileptology: 1977. Amsterdam: Swets & Zeitlinger, BV, 1978: 269–70
Redenbaugh JE, Sato S, Penry JK, et al. Sodium valproate: pharmacokinetics and effectiveness in treating intractable seizures. Neurology 1980; 30: 1–6
Windorfer A, Sauer W, Gadeke R. Elevation of diphenylhydantoin and primidone serum concentration by addition of dipropylacetate, a new anticonvulsant drug. Acta Paediatr Scand 1972; 64: 771–2
Cramer JA, Mattson RH. Valproic acid: in vitro plasma protein binding and interaction with phenytoin. Ther Drug Monit 1979; 1: 105–16
Knott C, Hamshaw-Thomas A, Reynolds F. Phenytoin-valproate interaction: importance of saliva monitoring in epilepsy. BMJ 1982; 284: 13–6
Suzuki Y, Nagai T, Mano T, et al. Interaction between valproate formulation and phenytoin concentrations. Eur J Clin Pharmacol 1995; 48: 61–3
Zagnoni P, Avanzini G, Baruzzi A, et al. Sodium 2-n-propyl pentanoate (2-PP) plasma concentrations in epileptic patients. Pharm Weekbl 1977; 112: 300–4
Henriksen O, Johannessen SI. Clinical and pharmacokinetic observations on sodium valproate: a 5-year follow-up study in 100 children with epilepsy. Acta Neurol Scand 1982; 65: 504–23
Cloyd JC, Kriel RL, Fischer JH, et al. Pharmacokinetics of valproic acid in children: I. Multiple antiepileptic drug therapy. Neurology 1983; 33: 185–91
Cloyd JC, Kriel RL, Fischer JH. Valproic acid pharmacokinetics in children: II. Discontinuation of concomitant antiepileptic drug therapy. Neurology 1985; 35: 1623–7
Kapetanovic IM, Kupferberg HJ, Porter RJ, et al. Mechanism of valproate-phenobarbital interaction in epileptic patients. Clin Pharmacol Ther 1981; 29: 480–6
Bernus I, Dickinson RG, Hooper WD, et al. Inhibition of phenobarbitone N-glucosidation by valproate. Br J Clin Pharmacol 1994; 38: 411–6
Patel IH, Levy RH, Cutler RE. Phenobarbital-valproic acid interaction in normal man. Clin Pharmacol Ther 1980; 27: 515–21
Loiseau P, Orgogozo JM, Centaud B, et al. Further pharmacokinetic observations on the interaction between phenobarbital and valproic acid in epileptic patients. In: Wada JA, Penry JK, editors. Advances in epileptology. Xth Epilepsy International Symposium; Vancouver; 1978 Sept. New York: Raven Press, 1980: 353–4
Bruni J, Wilder BJ, Perchalski RJ, et al. Valproic acid and plasma levels of phenobarbital. Neurology 1980; 30: 94–7
Schobben F, van der Kleijn D, Gabreels FJM. Pharmacokinetics of di-N-propylacetate in epileptic patients. Eur J Clin Pharmacol 1975; 8: 97–105
Richens A, Ahmad S. Controlled trial of sodium valproate. BMJ 1975; 4: 255–6
de Gatta MRF, Gonzales ACA, Sanchez MJG, et al. Effect of sodium valproate on phenobarbital serum levels in children and adults. Ther Drug Monit 1986; 8: 416–20
Suganuma T, Ishizaki T, Chiba K, et al. The effect of concurrent administration of valproate sodium on phenobarbital plasma concentration/dosage ratio in pediatric patients. J Pediatr 1981; 99: 314–7
Perucca E, Hedges A, Makki K, et al. A comparative study of the enzyme-inducing properties of anticonvulsant drugs in epileptic patients. Br J Clin Pharmacol 1984; 18: 401–10
Cereghino JJ, Van Meter JC, Brock JT, et al. Preliminary observations of serum carbamazepine concentrations in epileptic patients. Neurology 1973; 23: 357–66
Miyakoshi M. Aging variabilities of level-dose relationship in antiepileptic monopharmacy — with reference to drug interaction between mono- and bipharmacy. Jpn J Psychiatry Neurol 1986; 40: 329–35
Riva R, Contin M, Albani F, et al. Free concentration of carbamazepine and carbamazepine- 10,11-epoxide in children and adults: influence of age and phenobarbital co-medication. Clin Pharmacokinet 1985; 10: 524–31
Eylas AA, Patsalos PN, Agbato OA, et al. Factors influencing simultaneous concentrations of total and free carbamazepine and carbamazepine-10,11-epoxide in serum of children with epilepsy. Ther Drug Monit 1986; 8: 288–92
Rambeck B, May T, Juergens U. Serum concentrations of carbamazepine and its epoxide and diol metabolites in epileptic patients: the influence of dose and comedication. Ther Drug Monit 1987; 9: 298–303
Suzuki Y, Cox S, Hayes J, et al. Carbamazepine age-dose ratio relationship in children. Ther Drug Monit 1991; 13: 201–8
Tybring G, von Bahr C, Bertilsson L, et al. Metabolism of carbamazepine and its epoxide metabolite in human and rat liver in vitro. Drug Metab Dispos 1981; 9: 561–4
Wedlund PJ, Patel IH, Levy RH. Induction effect of phenobarbital on carbamazepine-10,11-epoxide kinetics in the rhesus monkey. J Pharmacokinet Biopharm 1982; 10: 427–35
Riva R, Contin M, Albani F, et al. Free and total serum concentrations of carbamazepine and carbamazepine-10,11 -epoxide in infancy and childhood. Epilepsia 1985; 26: 320–2
Korinthenberg R, Haug C, Hannak D. The metabolization of carbamazepine to CBZ-10,11-epoxide in children from the newborn age to adolescence. Neuropediatrics 1994; 25: 214–6
Adams DJ, Luders H, Pippenger C. Sodium valproate in the treatment of intractable seizure disorders: a clinical and electroencephalographic study. Neurology 1978; 28: 152–7
Bowdle TA, Levy RH, Cutler RE. Effects of carbamazepine on valproic acid kinetics in normal subjects. Clin Pharmacol Ther 1979; 26: 629–34
Jann MW, Fidone GS, Israel MK, et al. Increased valproate serum concentrations upon carbamazepine cessation. Epilepsia 1988; 29: 578–81
Panesar SK, Orr JM, Farrell K, et al. The effect of carbamazepine on valproic acid disposition in adult volunteers. Br J Clin Pharmacol 1989; 27: 323–8
Levy RH, Rettenmeier AW, Anderson GD, et al. Effects of poly-therapy with phenytoin, carbamazepine and stiripentol on formation of 4-ene valproate, a hepatotoxic metabolite of valproic acid. Clin Pharmacol Ther 1990; 48: 225–35
McKee PJW, Blacklaw J, Butler E, et al. Variability and clinical relevance of the interaction between sodium valproate and carbamazepine in epileptic patients. Epilepsy Res 1992; 11: 193–8
Levy RH, Moreland TA, Morselli PL, et al. Carbamazepine/valproic acid interaction in man and rhesus monkey. Epilepsia 1984; 25: 338–45
Robbins DK, Wedlund PJ, Kuhn R, et al. Inhibition of epoxide hydrolase by valproic acid in epileptic patients receiving carbamazepine. Br J Clin Pharmacol 1990; 29: 759–62
Svinarov DA, Pippenger CE. Valproic acid-carbamazepine interaction: is valproic acid a selective inhibitor of epoxide hydrolase? Ther Drug Monit 1995; 17: 217–20
Chang SL, Levy RH. Inhibitory effect of valproic acid on the disposition of carbamazepine and carbamazepine-10,11-epoxide in the rat. Drug Metab Dispos 1986; 14: 281–6
Kerr BM, Rettie AE, Eddy AC, et al. Inhibition of human liver microsomal epoxide hydrolase by valproate and valpromide: in vitro/in vivo correlation. Clin Pharmacol Ther 1989; 46: 82–93
Pisani F, Caputo M, Fazio A, et al. Interaction of carbamazepine 10,11-epoxide, an active metabolite of carbamazepine, with valproate: a pharmacokinetic study. Epilepsia 1990; 31: 339–42
Mattson GF, Mattson RH, Cramer JA. Interaction between valproic acid and carbamazepine: an in vitro study of protein binding. Ther Drug Monit 1982; 4: 181–4
Haidukewych D, Zielinski JJ, Rodin EA. Derivation and evaluation of an equation for prediction of free carbamazepine concentration in patients comedicated with valproic acid. Ther Drug Monit 1989; 11: 528–32
Hassan MN, Laljee HCK, Parsonage MJ. Sodium valproate in the treatment of resistant epilepsy. Acta Neurol Scand 1976; 54: 209–18
Jeavons PM, Clark JE, Maheswari MC. Treatment of generalized epilepsies of childhood and adolescence with sodium valproate (Epilim). Dev Med Child Neurol 1977; 19: 9–25
Lhermitte F, Marteau R, Serdaru M. Dipropylacetate (valproate de sodium) et carbamazepine: une association antiépileptique suspecte. Presse Med 1978; 7: 3780
Bourgeois BFD, Wad N. Individual and combined antiepileptic and neurotoxic activity of carbamazepine and carbamazepine-10, 11 -epoxide in mice. J Pharmacol Exp Ther 1984; 231: 411–5
Schoeman JF, Elyas AA, Brett EM, et al. Correlation between plasma carbamazepine-10,11 -epoxide concentration and drug side-effects in children with epilepsy. Dev Med Child Neurol 1984; 26: 756–64
Patsalos PN, Stephenson TJ, Krishna S, et al. Side-effects induced by carbamazepine-10,11 -epoxide. Lancet 1985; II: 496
Gillham RA, Williams N, Wiedmann K, et al. Concentration-effect relationships with carbamazepine and its epoxide on psychomotor and cognitive function in epileptic patients. J Neurol Neurosurg Psychiatry 1988; 51: 929–33
Theodore WH, Narang PK, Holmes MD, et al. Carbamazepine and its epoxide: relation of plasma levels to toxicity and seizure control. Ann Neurol 1989; 25: 194–6
Bertilsson L, Tomson T. Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine 10,11-epoxide: an update. Clin Pharmacokinet 1986; 11: 177–98
Fincham RW, Schottelius DD, Sahs AL. The influence of diphenylhydantoin on primidone metabolism. Arch Neurol 1974; 30: 259–62
Reynolds EH. Longitudinal studies of antiepileptic drug levels. Preliminary observations: interaction of phenytoin and primidone. In: Schneider H, Janz D, Gardner-Thorpe C, et al., editors. Clinical pharmacology of antiepileptic drugs. Berlin: Springer-Verlag, 1975: 79–85
Reynolds EH, Fenton G, Fenwick P, et al. Interaction of phenytoin and primidone. BMJ 1975; 14: 594–5
Schmidt D. The effect of phenytoin and ethosuximide on primidone metabolism in patients with epilepsy. J Neurol 1975; 209: 115–23
Callaghan N, Feely M, Duggan F, et al. The effect of anticonvulsant drugs which induce liver microsomal enzymes on derived and ingested phenobarbitone levels. Acta Neurol Scand 1977; 56: 1–6
Callaghan N, Duggan F, O’Hare J, et al. Serum levels of phenobarbitone and phenylethylmalonamide with primidone used as a single drug and in combination with carbamazepine or phenytoin. In: Johannessen SL, Morselli PL, Pippenger CE, et al., editors. Antiepileptic therapy: advances in drug monitoring. New York: Raven Press, 1980: 307–13
Cloyd JC, Miller KW, Leppik IE. Primidone kinetics: effect of concurrent drugs and duration of therapy. Clin Pharmacol Ther 1981; 29: 402–7
Lambie DG, Johnson RH. The effects of phenytoin on phenobarbitone and primidone metabolism. J Neurol Neurosurg Psychiatry 1981; 44: 148–51
Porro MG, Kupferberg HG, Porter RJ, et al. Phenytoin: an inhibitor and inducer of primidone metabolism in an epileptic patient. Br J Clin Pharmacol 1982; 14: 294–7
Syversen GB, Morgan JP, Weintraub M, et al. Acetazolamide-induced interference with primidone absorption. Case report and metabolic studies. Arch Neurol 1977; 34: 80–4
Warren JW, Benmaman JD, Wannamaker BB, et al. Kinetics of a carbamazepine-ethosuximide interaction. Clin Pharmacol Ther 1980; 28: 646–51
Battino D, Cusi C, Franceschetti S, et al. Ethosuximide plasma concentrations: influence of age and associated concomitant therapy. Clin Pharmacokinet 1982; 7: 176–80
Bachmann KA, Jauregui L. Use of single sample clearance estimates of cytochrome P450 substrates to characterize human hepatic CYP status in vivo. Xenobiotica 1993; 23: 307–15
Mattson RH, Cramer JA. Valproic acid and ethosuximide interaction. Ann Neurol 1980; 7: 583–4
Pisani F, Narbone MC, Trunfio C, et al. Valproic acid-ethosuximide interaction: a pharmacokinetic study. Epilepsia 1984; 25: 229–33
Smith GA, McKauge L, Dubety D, et al. Factors influencing plasma concentrations of ethosuximide. Clin Pharmacokinet 1979; 4: 38–52
Bauer LA, Harris C, Wilensky AJ, et al. Ethosuximide kinetics: possible interaction with valproic acid. Clin Pharmacol Ther 1982; 31: 741–5
Dawson GW, Brown HW, Clark BG. Serum phenytoin after ethosuximide. Ann Neurol 1978; 4: 583–4
Kumps A, Wurth C. Oxcarbazepine disposition: preliminary observations in patients. Biopharm Drug Dispos 1990; 11: 365–70
van Parys JAP, Meijer JWA, Segers JP. Dose-concentration proportionality in epileptic patients stabilized on oxcarbazepine: effects of co-medication [abstract]. Epilepsia 1991; 32 Suppl. 1: 70
Tartara A, Galimberti CA, Manni R, et al. The pharmacokinetic profile of oxcarbazepine and its active metabolite 10-hydroxy-carbamazepine in normal subjects and in epileptic patients treated with phenobarbitone or valproic acid. Br J Clin Pharmacol 1993; 36: 366–8
Hulsman JARJ, Rentmeester TW, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of the monohydroxy and dihydroxy metabolites of oxcarbazepine. Clin Pharmacol Ther 1995; 58: 383–9
McKee PJW, Blacklaw J, Forrest G, et al. A double-blind, placebo-controlled interaction study between oxcarbazepine and carbamazepine, sodium valproate and phenytoin in epileptic patients. Br J Clin Pharmacol 1994; 37: 27–32
Arnoldussen W, Hulsman J, Rentmeester T. Oxcarbazepine interactive with valproate? Clinical and pharmacokinetic study in several patient groups [abstract]. Epilepsia 1992; 33 Suppl. 3: 111
Larkin JG, McKee PJW, Forrest G, et al. Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects. Br J Clin Pharmacol 1991; 31: 65–71
Houtkooper MA, Lammertsma A, Meyer JWA, et al. Oxcarbazepine (GP 47680): a possible alternative to carbamazepine? Epilepsia 1987; 28: 693–8
Battino D, Croci D, Granata T, et al. Changes in unbound and total valproic acid concentrations after replacement of carbamazepine with oxcarbazepine. Ther Drug Monit 1992; 14: 376–9
Yuen AWC. Lamotrigine: interactions with other drugs. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 883–7
Binnie CD, van Emde Boas W, Kasteleijn-Nolste-Trenite DGA, et al. Acute effects of lamotrigine (BW430C) in persons with epilepsy. Epilepsia 1986; 27: 248–54
Jawad S, Yuen AWC, Peck AW, et al. Lamotrigine: single-dose pharmacokinetics and initial 1 week experience in refractory epilepsy. Epilepsy Res 1987; 1: 194–201
Cohen AF, Land GS, Breimer DD, et al. Lamotrigine, a new anticonvulsant: pharmacokinetics in normal humans. Clin Pharmacol Ther 1987; 42: 535–41
Binnie CD, Debets RMC, Engelsman M, et al. Double-blind crossover trial of lamotrigine (Lamictal) as add-on therapy in intractable epilepsy. Epilepsy Res 1989; 4: 222–9
Ramsay RE, Pellock JM, Garnett WR, et al. Pharmacokinetics and safety of lamotrigine (Lamictal) in patients with epilepsy. Epilepsy Res 1991; 10: 191–200
Wolf P. Lamotrigine: preliminary clinical observations on pharmacokinetics and interactions with traditional antiepileptic drugs. J Epilepsy 1992; 5: 73–9
Yuen AWC, Land G, Weatherley BC, et al. Sodium valproate inhibits lamotrigine metabolism. Br J Clin Pharmacol 1992; 33: 511–3
Yau MK, Wargin WA, Wolf KB, et al. Effect of valproate on pharmacokinetics of lamotrigine (Lamictal) at steady state [abstract]. Epilepsia 1992; 33 Suppl. 3: 82
Betts T, Goodwin G, Withers RM, et al. Human safety of lamotrigine. Epilepsia 1991; 32 Suppl. 2: 17–21
Graves NM, Ritter FJ, Wagner ML, et al. Effect of lamotrigine on carbamazepine epoxide concentrations [abstract]. Epilepsia 1991; 32 Suppl. 3: 13
Warner T, Patsalos PN, Prevett M, et al. Lamotrigine-induced carbamazepine toxicity: an interaction with carbamazepine-10,11-epoxide. Epilepsy Res 1992; 11: 147–50
Loiseau P, Yuen AWC, Duché B, et al. A randomised double-blind placebo-controlled crossover add-on trial of lamotrigine in patients with treatment-resistant partial seizures. Epilepsy Res 1990; 7: 136–45
Sander JWAS, Patsalos PN, Oxley JR, et al. A randomised double-blind placebo controlled add-on trial of lamotrigine in patients with severe epilepsy. Epilepsy Res 1990; 6: 221–6
Schapel GJ, Beran RG, Vajda FJE, et al. Double-blind, placebo controlled, crossover study of lamotrigine in treatment resistant partial seizures. J Neurol Neurosurg Psychiatry 1993; 56: 448–53
Pisani F, Xiao B, Fazio A, et al. Single dose pharmacokinetics of carbamazepine-10,11-epoxide in patients on lamotrigine monotherapy. Epilepsy Res 1994; 19: 245–8
Gidal BE, Zupanc ML. Potential pharmacokinetic interaction between felbamate and phenobarbital. Ann Pharmacother 1994; 28: 455–8
Fuerst RH, Graves NM, Leppik IE, et al. Felbamate increases phenytoin but decreases carbamazepine concentrations. Epilepsia 1988; 29: 488–91
Graves NM, Holmes GB, Fuerst RH, et al. Effect of felbamate on phenytoin and carbamazepine serum concentrations. Epilepsia 1989; 30: 225–9
Wagner ML, Graves NM, Leppik IE, et al. The effect of felbamate on valproic acid disposition. Clin Pharmacol Ther 1994; 56: 494–502
Leppik IE, Dreifuss FE, Pledger GW, et al. Felbamate for partial seizures: results of a controlled clinical trial. Neurology 1991; 41: 1785–9
Albani F, Theodore WH, Washington P, et al. Effect of felbamate on plasma levels of carbamazepine and its metabolites. Epilepsia 1991; 32: 130–2
Wagner ML, Remmel RP, Graves NM, et al. Effect of felbamate on carbamazepine and its major metabolites. Clin Pharmacol Ther 1993; 53: 536–43
Sachdeo R, Wagner M, Sachdeo S, et al. Steady-state pharmacokinetics of phenytoin when coadministered with Felbatol (felbamate) [abstract]. Epilepsia 1992; 33 Suppl. 3: 84
Colucci R, Glue P, Holt B, et al. Effect of felbamate on the pharmacokinetics of lamotrigine. J Clin Pharmacol 1996; 36: 634–8
Wagner ML, Graves NM, Marienau K, et al. Discontinuation of phenytoin and carbamazepine in patients receiving felbamate. Epilepsia 1991; 32: 398–406
Sachdeo R, Wagner M, Sachdeo S, et al. Steady-state pharmacokinetics of Felbatol (felbamate) when coadministered with phenytoin [abstract]. Epilepsia 1992; 33 Suppl. 3: 84
Wilensky AJ, Friel PN, Ojemann LM, et al. Pharmacokinetics of W-554 (ADD 03055) in epileptic patients. Epilepsia 1985; 26: 602–6
Rimmer EM, Richens A. Double-blind study of gamma-vinyl GABA in patients with refractory epilepsy. Lancet 1984; I: 189–90
Browne TR, Mattson RH, Penry JK, et al. Vigabatrin for refractory complex partial seizures: multicenter single-blind study with long-term follow-up. Neurology 1987; 37: 184–9
Rimmer EM, Richens A. Interaction between vigabatrin and phenytoin. Br J Clin Pharmacol 1989; 27 Suppl. 1: 27–33
Doose DR, Walker SA, Sachedeo R, et al. Steady-state pharmacokinetics of Tegretol (carbamazepine) and Topamax (Topiramate) in patients with epilepsy on monotherapy, and during combination therapy [abstract]. Epilepsia 1994; 35 Suppl. 8: 54
Gisclon LG, Curtis CR, Kramer LD. The steady-state (ss) pharmacokinetics (pk) of phenytoin (dilantin) and topiramate (topamax) in epileptic patients on monotherapy, and during combination therapy [abstract]. Epilepsia 1994; 35 Suppl. 8: 54
Wilensky AJ, Ojemann LM, Chmelir T, et al. Topiramate pharmacokinetics in epileptic patients receiving carbamazepine [abstract]. Epilepsia 1989; 30: 645–6
Doose DR, Walker SA, Pledger G, et al. Evaluation of phenobarbital and primidone/phenobarbital (primidone’s active metabolite) plasma concentrations during administration of add-on topiramate therapy in five multicenter, double-blind, placebo-controlled trials in outpatients with partial seizures [abstract]. Epilepsia 1995; 36 Suppl. 3: 158
Guidolin L, Canevini MP, Sgro V, et al. Topiramate as add-on therapy in drug-resistant partial epilepsies [abstract]. Epilepsia 1995; 36 Suppl. 3: 151
Ojemann LM, Shastri RA, Wilensky AJ, et al. Comparative pharmacokinetics of zonisamide (CI-912) in epileptic patients on carbamazepine or phenytoin monotherapy. Ther Drug Monit 1986; 8: 293–6
Schentag JJ, Gengo FM, Wilton JH, et al. Influence of phenobarbital, cimetidine, and renal disease on zonisamide kinetics [abstract]. Pharm Res 1987; Suppl. 4: 79s
Kimura M, Tanaka N, Kimura Y, et al. Pharmacokinetic interaction of zonisamide in rats: effect of other antiepileptics on zonisamide. J Pharmacobiodyn 1992; 15: 631–9
Abo J, Miura H, Takanashi S, et al. Drug interaction between zonisamide and carbamazepine: a pharmacokinetic study in children with cryptogenic localization-related epilepsies [abstract]. Epilepsia 1995; 36 Suppl. 3: S162
Sackellares JC, Donofrio PD, Wagner JG, et al. Pilot study of zonisamide (1,2-benzisoxazole-3-methanesulfonamide) in patients with refractory partial seizures. Epilepsia 1985; 26: 206–11
Minami T, Ieiri I, Ohtsubo K, et al. Influence of additional therapy with zonisamide (Excegran) on protein binding and metabolism of carbamazepine. Epilepsia 1994; 35: 1023–5
Browne TR, Szabo GK, Kres J, et al. Drug interactions of zonisamide (CI-912) with phenytoin and carbamazepine [abstract]. J Clin Pharmacol 1986; 26: 555
Hammond EJ, Perchalski RJ, Wilder BJ. Neuropharmacology of zonisamide, a new antiepileptic drug. Gen Pharmacol 1987; 18: 303–7
Schmidt D, Jacob R, Loiseau P, et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res 1993; 15: 67–73
Tasaki K, Minami T, Ieiri I, et al. Drug interactions of zonisamide with phenytoin and sodium valproate: serum concentrations and protein binding. Brain Dev 1995; 17: 182–5
Homan RW, Rosenberg HC. Benzodiazepines. In: Wyllie E, editor. The treatment of epilepsy. Philadelphia: Lea and Febiger, 1993: 932–49
Levy RH, Lane EA, Guyot M, et al. Analysis of parent drug-metabolite relationship in the presence of an inducer. Application to the carbamazepine-clobazam interaction in normal man. Drug Metab Dispos 1983; 11: 286–92
Jawad S, Richens A, Oxley J. Single dose pharmacokinetic study of clobazam in normal volunteers and epileptic patients. Br J Clin Pharmacol 1984; 18: 873–7
Bardy AH, Seppala T, Salokorpi T, et al. Monitoring of concentrations of clobazam and norclobazam in serum and saliva of children with epilepsy. Brain Dev 1991; 13: 174–9
Dhillon S, Richens A. Pharmacokinetics of diazepam in epileptic patients and normal volunteers following intravenous administration. Br J Clin Pharmacol 1981; 12: 841–4
Perucca E. Pharmacokinetic interactions with antiepileptic drugs. Clin Pharmacokinet 1982; 7: 57–84
Nanda RN, Johnson RH, Keogh HJ, et al. Treatment of epilepsy with clonazepam and its effect on other anticonvulsants. J Neurol Neurosurg Psychiatry 1977; 40: 538–43
Lai AA, Levy RH, Cutler RE. Time-course of interaction between carbamazepine and clonazepam in normal man. Clin Pharmacol Ther 1978; 24: 316–23
Sjo O, Hvidberg EF, Naestoft J, et al. Pharmacokinetics and side effects of clonazepam and its 7-amino metabolite in man. Eur J Clin Pharmacol 1975; 8: 249–54
Khoo K, Mendels J, Rothbart M, et al. Influence of phenytoin and phenobarbital on the disposition of a single oral dose of clonazepam. Clin Pharmacol Ther 1980; 28: 368–75
Hvidberg EF, Sjo O. Clinical pharmacokinetic experiences with clonazepam. In: Schneider H, Janz D, Gardner-Thorpe C, et al., editors. Clinical pharmacology of anti-epileptic drugs. Berlin: Springer-Verlag, 1975: 242–6
Wilensky AJ, Ojemann LM, Temkin NR, et al. Clorazepate kinetics in treated epileptics. Clin Pharmacol Ther 1978; 24: 22–30
Sennoune S, Mesdjian E, Bonneton J, et al. Interaction between clobazam and standard antiepileptic drugs in patients with epilepsy. Ther Drug Monit 1992; 14: 269–74
Dhillon S, Richens A. Serum protein binding of diazepam and its displacement by valproic acid in vitro. Br J Clin Pharmacol 1981; 12: 591–2
Menke G, Pfister P, Sauerwein S, et al. Age-dependence and free fatty acid modulation of binding kinetics at the benzodiazepine binding site of serum albumin in neonates and adults determined using fast reaction methods. Br J Clin Pharmacol 1987; 23: 439–45
Anderson GD, Gidal BE, Kantor ED, et al. Lorazepam-valproate interaction: studies in normal subjects and isolated perfused rat liver. Epilepsia 1994; 35: 221–5
Dhillon S, Richens A. Valproic acid and diazepam interaction in vivo. Br J Clin Pharmacol 1982; 13: 553–60
Sobaniec W, Sobaniec H, Sobaniec-Lotowska M, et al. Interaction of valproate with other antiepileptic drugs in children treated for epilepsy [abstract]. Epilepsia 1995; 36 Suppl. 3: 68
Jeavons PM, Clark JE. Sodium valproate in treatment of epilepsy. BMJ 1974; 2: 584–6
Jeavons PM. Choice of drug therapy in epilepsy. Practitioner 1977; 219: 542–56
Perucca E, Manzo L, Crema A. Pharmacokinetic interactions between antiepileptic and psychotropic drugs. In: Trimble MR, editor. The psychopharmacology of epilepsy. Chichester: John Wiley & Sons, 1985: 95–105
Goggin T, Callaghan N. Blood levels of clobazam and its metabolites and therapeutic effect. In: Hindmarch I, Stonier PD, Trimble MR, editors. Clobazam: human psychopharmacology and clinical applications. London: Royal Society of Medicine, 1985: 149–53
Vajda FJE, Prineas RJ, Lowell RRH. Interaction between phenytoin and the benzodiazepines. BMJ 1971; 1: 346
Huang CY, McLead JG, Sampson D, et al. Clonazepam in the treatment of epilepsy. Med J Aust 1974; 2: 5–8
Inami M, Hara T. The effects of clonazepam on the plasma diphenylhydantoin level in epileptic patients [abstract]. Electroencephalogr Clin Neurophysiol 1977; 43: 497
Saavedra IN, Aguilera LI, Faure E, et al. Phenytoin/clonazepam interaction. Ther Drug Monit 1985; 7: 481–4
Collaborative Group for Epidemiology of Epilepsy. Adverse reactions to antiepileptic drugs: a multicenter survey of clinical practice. Epilepsia 1986; 27: 323–30
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Riva, R., Albani, F., Contin, M. et al. Pharmacokinetic Interactions Between Antiepileptic Drugs. Clin-Pharmacokinet 31, 470–493 (1996). https://doi.org/10.2165/00003088-199631060-00005
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199631060-00005