Skip to main content
SpringerLink
Log in

Clinical Pharmacokinetics and Pharmacological Effects of Carbamazepine and Carbamazepine-10,11-Epoxide

An update

  • Research Review
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Summary

Carbamazepine is a first-line drug in the treatment of most forms of epilepsy and also the drug of first choice in trigeminal neuralgia. Furthermore, it is now frequently used in bipolar depression.

Most oral formulations of carbamazepine are well absorbed with high bioavailability. The drug is 75% bound to plasma proteins. The degree of protein binding shows little variation between different subjects, and there is no need to monitor free rather than total plasma concentrations.

Carbamazepine is metabolised in the liver by oxidation before excretion in the urine. A major metabolite is carbamazepine-10,11-epoxide which is further metabolised by hydration before excretion. This epoxide-diol pathway is induced during long term treatment with carbamazepine. Co-medication with phenytoin or phenobarbitone further induces this metabolic pathway. Some but not all studies indicate an increased metabolism of carbamazepine during pregnancy. The drug crosses the placenta, and the newborns who are exposed to the drug during fetal life eliminate the drug readily after birth. There seems to be no problem to nurse children during treatment with carbamazepine. Metabolism of carbamazepine is comparable in children and adults.

Several studies have tried to establish a relationship between plasma carbamazepine and clinical effect in epilepsy, but very few of these are controlled. The best anticonvulsant effect seems to be obtained at plasma concentrations of 15 to 40 µmol/L and a similar optimal plasma concentration range was found in a controlled study in trigeminal neuralgia. Side effects are more frequent at higher plasma concentrations but are also seen within that range. In some patients, with pronounced fluctuation of plasma concentrations during the dosage interval, side effects may be avoided by more frequent dosing.

Carbamazepine-10,11-epoxide is a potent anticonvulsant in animal models. During treatment with carbamazepine the plasma concentrations of this metabolite are usually 10 to 50% of those of the parent drug. It has not been possible to establish the relative contribution of the two compounds to the pharmacological effects. The epoxide has therefore been given to humans with the aim of determining the relative potency of the parent drug and its metabolite. After single oral doses of carbamazepine-10,11-epoxide to healthy subjects, the compound was rapidly absorbed. As a mean of 90% of the given dose was recovered in urine as trans-10,11-dihydroxy-10,11-dihydro-carbamazepine, a complete absorption of unchanged epoxide was shown. The mean plasma half-life of unchanged epoxide was 6.1 hours with a mean volume of distribution of 0.74 L/kg.

Six patients with trigeminal neuralgia had their optimal carbamazepine dose replaced with carbamazepine-10,11-epoxide for 3 to 6 days. The study was single-blind and placebo controlled. When carbamazepine and the epoxide were given in similar doses, the pain control was comparable. The results show that during carbamazepine therapy, the contribution of the epoxide to the effect is considerable. No side effect was seen during the epoxide therapy. Further studies on the effect of carbamazepine-10,11-epoxide administration in epilepsy are indicated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Albright PS, Bruni J. Effects of carbamazepine and its epoxide metabolite on amygdala-kindled seizures in rats. Neurology 34: 1383–1386, 1984

    Article  PubMed  CAS  Google Scholar 

  • Bardy AH. Plasma clearances of phenytoin, phenobarbitone, primidone and carbamazepine during pregnancy: A prospective study. In Janz et al. (Eds) Epilepsy, pregnancy and the child, pp. 141–145, Raven Press, New York, 1981

    Google Scholar 

  • Battino D, Binelli S, Bossi L, Canger R, Croci D, et al. Plasma concentrations of carbamazepine and carbamazepine-10,11-epoxide during pregnancy and after delivery. Clinical Pharmacokinetics 10: 279–284, 1985

    Article  PubMed  CAS  Google Scholar 

  • Bertilsson L. Clinical pharmacokinetics of carbamazepine. Clinical Pharmacokinetics 3: 128–143, 1978

    Article  PubMed  CAS  Google Scholar 

  • Bertilsson L, Höjer B, Tybring G, Osterloh J, Rane A. Autoinduction of carbamazepine metabolism in children examined by a stable isotope technique. Clinical Pharmacology and Therapeutics 27: 83–88, 1980

    Article  PubMed  CAS  Google Scholar 

  • Bertilsson L, Rane A. Methods for the determination of carbamazepine and its epoxide metabolite. In Johannessen et al. (Eds) Antiepileptic therapy: advances in drug monitoring, pp. 325–330, Raven Press, New York, 1980

    Google Scholar 

  • Bertilsson L, Tomson T, Tybring G. Pharmacokinetics: time-dependent changes (autoinduction of carbamazepine epoxidation). Journal of Clinical Pharmacology, in press, 1986

    Google Scholar 

  • Blennow G. Adverse effects from the circadian fluctuations of carbamazepine plasma levels. Acta Paediatrica Scandinavica 72: 397–401, 1983

    Article  PubMed  CAS  Google Scholar 

  • Bourgeois BFD, Wad N. Carbamazepine-10,11-diol steady-state serum levels and renal excretion during carbamazepine therapy in adults and children. Therapeutic Drug Monitoring 6: 259–265, 1984a

    Article  PubMed  CAS  Google Scholar 

  • Bourgeois BFD, Wad N. Individual and combined antiepileptic and neurotoxic activity of carbamazepine and carbamazepine-10,11-epoxide in mice. Journal of Pharmacology and Experimental Therapeutics 2: 411–415, 1984b

    Google Scholar 

  • Braun R, Dittmar W, Machut M, Weickmann S. Valepotriate mit Epoxidstruktur-beachtliche Alkylantien. Deutsche Apotheker Zeitung 122: 1109–1113, 1982

    CAS  Google Scholar 

  • Brodie MJ, Forrest G, Rapeport WG. Carbamazepine-10,11-epoxide concentrations in epileptics on carbamazepine alone and in combination with other anticonvulsants. British Journal of Clinical Pharmacology 16: 747–750, 1983

    Article  PubMed  CAS  Google Scholar 

  • Callaghan N, O’Callaghan M, Duggan B, Feely M. Carbamazepine as a single drug in the treatment of epilepsy. Journal of Neurology, Neurosurgery and Psychiatry 41: 907–912, 1978

    Article  CAS  Google Scholar 

  • Callaghan N, Kenny RA, O’Neill B, Crowley M, Goggin T. A prospective study between carbamazepine, phenytoin and sodium valproate as monotherapy in previously untreated and recently diagnosed patients with epilepsy. Journal of Neurology, Neurosurgery and Psychiatry 48: 639–644, 1985

    Article  CAS  Google Scholar 

  • Christiansen J, Dam M. Influence of phenobarbital and diphenylhydantoin on plasma carbamazepine levels in patients with epilepsy. Acta Neurologica Scandinavica 49: 543–546, 1973

    Article  PubMed  CAS  Google Scholar 

  • Contin M, Riva R, Albani F, Perucca E, Lamontanara G, et al. Alpha1-acid glycoprotein concentration and serum protein binding of carbamazepine and carbamazepine-10,11-epoxide in children with epilepsy. European Journal of Clinical Pharmacology 29: 211–214, 1985

    Article  PubMed  CAS  Google Scholar 

  • Dam M, Christiansen J. Carbamazepine (Tegretol) in the treatment of grand mal epilepsy. In Janz (Ed.) Epileptology: proceedings of the seventh International Symposium on Epilepsy, pp. 175–179, Georg Thieme Verlag, Berlin, 1976

    Google Scholar 

  • Dam M, Christiansen J. Interaction of propoxyphene with carbamazepine. Lancet 2: 509, 1977

    Article  PubMed  CAS  Google Scholar 

  • Dam M, Christiansen J, Munck O, Mygind KI. Antiepileptic drugs: metabolism in pregnancy. Clinical Pharmacokinetics 4: 53–62, 1979

    Article  PubMed  CAS  Google Scholar 

  • Dam M, Molin Christensen J, Brandt J, Stensgaard Hansen B, Hvidberg EF, et al. Antiepileptic drugs: interaction with dextropropoxyphene. In Johannessen et al. (Eds) Antiepileptic therapy: advances in drug monitoring, pp. 299–306, Raven Press, New York, 1980

    Google Scholar 

  • Dam M, Sury J, Christiansen J. Has carbamazepine-10,11-epoxide an independent antiepileptic effect in man? In Penry (Ed.) Epilepsy, Eighth International Symposium, pp. 143–146, Raven Press, New York, 1977

    Google Scholar 

  • Eichelbaum M, Bertilsson L. Determination of carbamazepine and its epoxide metabolite in plasma by high-speed liquid chromatography. Journal of Chromatogrphy 103: 135–140, 1975

    Article  CAS  Google Scholar 

  • Eichelbaum M, Bertilsson L, Lund L, Palmér L, Sjöqvist F. Plasma levels of carbamazepine and carbamazepine-10,11-epoxide during treatment of epilepsy. European Journal of Clinical Pharmacology 9: 417–421, 1976

    Article  CAS  Google Scholar 

  • Eichelbaum M, Ekbom K, Bertilsson L, Ringberger VA, Rane A. Plasma kinetics of carbamazepine and its epoxide metabolite in man after single and multiple doses. European Journal of Clinical Pharmacology 8: 337–341, 1975

    Article  PubMed  CAS  Google Scholar 

  • Eichelbaum M, Jensen C, von Sassen W, Bertilsson L, Tomson T. In vivo and in vitro biotransformation of carbamazepine in man and rat. In Levy et al. (Eds). Metabolism of antiepileptic drugs, pp. 27–32, Raven Press, New York, 1984

    Google Scholar 

  • Eichelbaum M, Köthe KW, Hoffmann F, von Unruh GE. Kinetics and metabolism of carbamazepine during combined antiepileptic drug therapy. Clinical Pharmacology and Therapeutics 26: 366–371, 1979

    PubMed  CAS  Google Scholar 

  • Eichelbaum M, Tomson T, Tybring G, Bertilsson L. Carbamazepine metabolism in man: induction and pharmacogenetic aspects. Clinical Pharmacokinetics 10: 80–90, 1985

    Article  PubMed  CAS  Google Scholar 

  • Faigle JW, Feldmann KF. Carbamazepine biotransformation: in Woodbury et al. (Eds) Antiepileptic drugs, 2nd ed., pp. 483–495, Raven Press, New York, 1982

    Google Scholar 

  • Faigle JW, Feldmann KF, Baltzer V. Anticonvulsant effect of carbamazepine. An attempt to distinguish between the potency of the parent drug and its epoxide metabolite. In Garner-Thorpe et al. (Eds) Antiepileptic drug monitoring, pp. 104–108, Pitman Press, Avon, 1977

    Google Scholar 

  • Frigerio A, Morselli PL. Carbamazepine: biotransformation. In Penry et al. (Eds) Advances in neurology 11, pp. 295–306, Elsevier, New York, 1975

    Google Scholar 

  • Friis ML, Christiansen J. Carbamazepine, carbamazepine-10,11-epoxide and phenytoin concentrations in brain tissue of epileptic children. Acta Neurologica Scandinavica 58: 104–108, 1978

    Article  PubMed  CAS  Google Scholar 

  • Friis ML, Christiansen J, Hvidberg EF. Brain concentrations of carbamazepine and carbamazepine-10,11-epoxide in epileptic patients. European Journal of Clinical Pharmacology 14: 47–51, 1978

    Article  PubMed  CAS  Google Scholar 

  • Froescher W, Eichelbaum M, Niesen M, Dietrich K, Rausch P. Carbamazepine levels in breast milk. Therapeutic Drug Monitoring 6: 266–271, 1984

    Article  PubMed  CAS  Google Scholar 

  • Froescher W, Niesen M, Altmann D, Eichelbaum M, Gugler R, et al. Antiepileptika — Therapie während der Schwangerschaft und Geburt. In Remschmidt et al. (Eds) Epilepsie 1980, pp. 152–163, Georg Thieme, Stuttgart, 1981

    Google Scholar 

  • Ghose K, Fry DE, Christfides JA. Effect of dosage frequency of carbamazepine on drug serum levels in epileptic patients. European Journal of Clinical Pharmacology 24: 375–381, 1983

    Article  PubMed  CAS  Google Scholar 

  • Glatt HR, Oesch F, Frigerio A, Garattini S. Epoxides metabolically produced from some known carcinogens and from some clinically used drugs, I. Differences in mutagenicity, International Journal of Cancer 16: 787–797, 1975

    CAS  Google Scholar 

  • Hansen JM, Siersback-Nielsen K, Skovsted L. Carbamazepineinduced acceleration of diphenylhydantoin and warfarin metabolism in man. Clinical Pharmacology and Therapeutics 12: 539–543, 1971

    PubMed  CAS  Google Scholar 

  • Hansten PD. Drug interactions — clincial significance of drug-drug interactions. Lea & Febiger, Philadelphia, 1985

    Google Scholar 

  • Hedrick R, Williams F, Morin R, Lamb WA, Cale IV JC. Carbamazepine-erythromycin interaction leading to carbamazepine toxicity in four epileptic children. Therapeutic Drug Monitoring 5: 405–407, 1983

    Article  PubMed  CAS  Google Scholar 

  • Hempel E, Klinger W. Drug stimulated biotransformation of hormonal steroid contraceptives: clinical implications. Drugs 12: 442–448, 1976

    Article  PubMed  CAS  Google Scholar 

  • Hooper WD, Dubetz DK, Eadie MJ, Tyrer JH. Preliminary observations on the clinical pharmacology of carbamazepine (Tegretol). Proceedings of the Australian Association of Neurologists 11: 189–198, 1974

    PubMed  CAS  Google Scholar 

  • Hooper WD, King AR, Patterson M, Dickinson RG, Eadie MJ. Simultaneous plasma carbamazepine and carbamazepine epoxide concentrations in pharmacokinetic and bioavailability studies. Therapeutic Drug Monitoring 7: 36–40, 1985

    Article  PubMed  CAS  Google Scholar 

  • Höppener RJ, Kuyer A, Meijer JWA, Hulsman J. Correlation between daily fluctuations of carbamazepine serum levels and intermittent side effects. Epilepsia 21: 341–350, 1980

    Article  PubMed  Google Scholar 

  • Jann MW, Ereswepwy L, Saklad SR, Seidel DR, Davis CM, et al. Effects of carbamazepine on plasma haloperidol levels. Journal of Clinical Psychopharmacology 5: 106–109, 1985

    Article  PubMed  CAS  Google Scholar 

  • Johannessen SI, Baruzzi A, Gomeni R, Strandjord RE, Morselli PL. Further observations on carbamazepine and carbamazepine-10,11-epoxide kinetics in epileptic patients. In Gardner Thorpe et al. (Eds) Antiepileptic drug monitoring pp. 110–124, Pitman, London, 1977

    Google Scholar 

  • Johannessen SI, Gerna M, Bakke J, Strandjord RE, Morselli PL. CSF concentrations and serum protein binding of carbamazepine and carbamazepine-10,11-epoxide in epileptic patients. British Journal of Clinical Pharmacology 3: 575–582, 1976

    Article  PubMed  CAS  Google Scholar 

  • Kaneko S, Sato T, Suzuki K. The levels of anticonvulsants in breast milk. British Journal Clinical Pharmacology 7: 624–627, 1979

    Article  CAS  Google Scholar 

  • Kaneko S, Suzuki K, Sato T, Ogawa Y, Nomura Y. The problems of antiepileptic medication in the neonatal period: is breast-feeding advisable? In Janz et al. (Eds) Epilepsy, pregnancy and the child, pp. 343–347, Raven Press, New York, 1982

    Google Scholar 

  • Kidron R, Averbuch I, Klein E, Belmaker RH. Carbamazepineinduced reduction of blood levels of haloperidol in chronic schizophrenia. Biological Psychiatry 20: 199–228, 1985

    Article  Google Scholar 

  • Klein E, Bental E, Lerer B, Belmaker RH. Carbamazepine and haloperidol vs placebo and haloperidol in excited psychosis. Archives of General Psychiatry 41: 165–170, 1984

    Article  PubMed  CAS  Google Scholar 

  • Königstein M, Larisch M, Obe G. Mutagenicity of antiepileptic drugs. I Carbamazepine and some of its metabolites. Mutation Research 139: 83–86, 1984

    PubMed  Google Scholar 

  • Krämer G, Besser R, Theisohn M, Eichelbaum M. Carbamaze-pine-danazol drug interaction: mechanism and therapeutic usefulness. Acta Neurologica Scandinavica 70: 249, 1984

    Google Scholar 

  • Kuhnz W, Jäger-Roman E, Rating D, Deichl A, Kunze J, et al. Carbamazepine and carbamazepine-10,11-epoxide during pregnancy and postnatal period in epileptic mothers and their nursed infants: pharmacokinetics and clinical effects. Pediatric Pharmacology 3: 199–208, 1983

    PubMed  CAS  Google Scholar 

  • Kuhnz W, Steldinger R, Nau H. Protein binding of carbamazepine and its epoxide in maternal and fetal plasma at delivery: comparison to other anticonvulsants. Developmental Pharmacology and Therapeutics 7: 61–72, 1984

    PubMed  CAS  Google Scholar 

  • Kumps AH. Dose-dependency of the ratio between carbamazepine serum level and dosage in patients with epilepsy. Therapeutic Drug Monitoring 3: 271–274, 1981

    Article  PubMed  CAS  Google Scholar 

  • Kumps A. Simultaneous HPLC determination of oxcarbazepine, carbamazepine and their metabolites in serum. Journal of Liquid Chromatography 7: 1235–1241, 1984

    Article  CAS  Google Scholar 

  • Kutt H. Interactions between anticonvulsants and other commonly prescribed drugs. Epilepsia 25 (Suppl. 2): S118–S131, 1984

    Article  PubMed  Google Scholar 

  • Kutt H, Solomon G, Wasterlain C, Peterson H, Louis S, et al. Carbamazepine in difficult to control epileptic out-patients. Acta Neurologica Scandinavica 60 (Suppl.): 27–32, 1975

    Article  PubMed  CAS  Google Scholar 

  • Lai AA, Levy RH, Cutler RE. Time course of interaction between carbamazepine and clonazepam in normal man. Clinical Pharmacology and Therapeutics. 24: 316–323, 1978

    PubMed  CAS  Google Scholar 

  • Lertratanangkoon K, Horning MG. Metabolism of carbamazepine. Drug Metabolism and Disposition 10: 1–10, 1982

    PubMed  CAS  Google Scholar 

  • Lesser RP, Pippenger CE, Lüders H, Dinner DS. High-dose monotherapy in treatment of intractable seizures. Neurology 34: 707–711, 1984

    Article  PubMed  CAS  Google Scholar 

  • Levine M, Jones MW, Sheppard I. Differential effect of cimetidine on serum concentrations of carbamazepine and phenytoin. Neurology 35: 562–565, 1985

    Article  PubMed  CAS  Google Scholar 

  • Levy RH, Moreland TA, Morselli PL, Guyot M, Brachet-Liermain A, et al. Carbamazepoine/valproic acid interaction in man and rhesus monkey. Epilepsia 25: 338–345, 1984

    Article  PubMed  CAS  Google Scholar 

  • Levy RH, Schmidt D. Utility of free level monitoring of antiepileptiac drugs. Epilepsia 26: 199–205, 1985

    Article  PubMed  CAS  Google Scholar 

  • Lindhout D, Höppener RJEA, Meinardi H. Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia 25: 77–83, 1984

    Article  PubMed  CAS  Google Scholar 

  • MacKichan JJ. Simultaneous liquid Chromatographic analysis for carbamazepine and carbamazepine-10,11-epoxide in plasma and saliva by use of double internal standardization. Journal of Chromatography 181: 373–383, 1980

    Article  PubMed  CAS  Google Scholar 

  • MacKichan JJ, Duffner PK, Cohen ME. Salivary concentrations and plasma protein binding of carbamazepine and carbamazepine-10,11-epoxide in epileptic patients. British Journal of Clinical Pharmacology 12: 31–37, 1981

    Article  PubMed  CAS  Google Scholar 

  • Mattson GF, Mattson RH, Cramer JA. Interaction between valproic acid and carbamazepine: an in vitro study of protein binding. Therapeutic Drug Monitoring 4: 181–184, 1982

    Article  PubMed  CAS  Google Scholar 

  • McKauge L, Tyrer JH, Eadie MJ. Factors influencing simultaneous concentrations of carbamazepine and its epoxide in plasma. Therapeutic Drug Monitoring 3: 63–70, 1981

    PubMed  CAS  Google Scholar 

  • Meijer JWA, Binnie CD, Debets RMC, van Parys JAP, DeBeer-Pawlikowski NKB. Possible hazard of valpromide-carba-mazepine combinations therapy in epilepsy. Lancet 1: 802, 1984

    Article  PubMed  CAS  Google Scholar 

  • Meijer JWA, Rambeck B, Riedman M. Antiepileptic drug monitoring by Chromatographic methods and immunotechniques — comparison of analytical performance, practability, and economy. Therapeutic Drug Monitoring 5: 39–53, 1983

    Article  PubMed  CAS  Google Scholar 

  • Mesdjian E, Dravet C, Cenraud B, Roger J. Carbamazepine intoxication due to triacetyloleandomycin administration in epileptic patients. Epilepsia 21: 489–496, 1980

    Article  PubMed  CAS  Google Scholar 

  • Mikkelsen B, Berggreen P, Joensen P, Kristensen O, Køhler O, et al. Clonazepam (Rivotril) and carbamazepine (Tegretol) in psychomotor epilepsy: a randomized multicenter trial. Epilepsia 22: 415–420, 1981

    Article  PubMed  CAS  Google Scholar 

  • Monaco F, Piredda S. Carbamazepine-10,11-epoxide determined by EMIT carbamazepine reagent. Epilepsia 21: 475–477, 1980

    Article  PubMed  CAS  Google Scholar 

  • Morselli PL, Baruzzi A, Gerna M, Bossi L, Porta M. Carbamazepine and carbamazepine-10,11-epoxide concentrations in human brain. British Journal of Clinical Pharmacology 4: 535–540, 1977

    Article  PubMed  CAS  Google Scholar 

  • Morselli PL, Gerna M, de Maio D, Zanda G, Viani F, et al. Pharmacokinetic studies on carbamazepine in volunteers and in epileptic patients. In Schneider et al. (Eds) Clinical pharmacology of antiepileptic drugs, pp. 166–180, Springer, Berlin, 1975

    Chapter  Google Scholar 

  • Nau H, Kuhnz W, Egger H-J, Rating D, Helge H. Anticonvulsants during pregnancy and lactation — transplacental, maternal and neonatal pharmacokinetics. Clinical Pharmacokinetics 7: 508–543, 1982

    Article  PubMed  CAS  Google Scholar 

  • Neuvonen PJ. Bioavailability and central side effects of different carbamazepine tablets. Journal of Clinical Pharmacology, Therapeutics and Toxicology 23: 226–232, 1985

    CAS  Google Scholar 

  • Neuvonen PJ, Elonen E. Effect of activated charcoal on absorption and elimination of phenobarbitone, carbamazepine and phenylbutazone in man. European Journal of Clinical Pharmacology 17: 52–57, 1980

    Article  Google Scholar 

  • Otani K. Risk factors for the increased seizure frequency during pregnancy and puerperium. Folia Psychiatrica Neurologica Japonica 39: 33–41, 1985

    CAS  Google Scholar 

  • Pacifici GM, Tomson T, Bertilsson L, Rane A. Valpromide/carbamazepine and risk of teratogenicity. Lancet 1: 397–398, 1985

    Article  PubMed  CAS  Google Scholar 

  • Paxton JW, Aman MG, Werry JS. Fluctuations in salivary carbamazepine and carbamazepine-10,11-epoxide concentrations during the day in epileptic children. Epilepsia 24: 716–724, 1983

    Article  PubMed  CAS  Google Scholar 

  • Penttila O, Neuvonen PJ, Aho K, Lehtovaara R. Interaction between doxycycline and some antiepileptic drugs. British Medical Journal 2: 470–472, 1974

    Article  PubMed  CAS  Google Scholar 

  • Perucca E. Pharmacokinetic interactions with antiepileptic drug. Clinical Pharmacokinetics 7: 57–84, 1982

    Article  PubMed  CAS  Google Scholar 

  • Perucca E. Free level monitoring of antiepileptic drugs — clinical usefulness and case studies. Clinical Pharmacokinetics 9 (Suppl. 1): 71–78, 1984

    Article  PubMed  Google Scholar 

  • Perucca E, Bittencourt P, Richens A. Effect of dose increments on serum carbamazepine concentration in epileptic patients. Clinical Pharmacokinetics 5: 576–582, 1980

    Article  PubMed  CAS  Google Scholar 

  • Perucca E, Richens A. Water intoxication produced by carbamazepine and its reversal by phenytoin. Journal of Neurology, Neurosurgery and Psychiatry 43: 540–545, 1980

    Article  CAS  Google Scholar 

  • Piafsky KM, Rane A. Formation of carbamazepine epoxide in human fetal liver. Drug Metabolism and Disposition 6: 502, 1978

    PubMed  CAS  Google Scholar 

  • Post RM, Uhde TW, Ballenger JC. The efficacy of carbamazepine in affective illness. In Usdin et al. (Eds) Frontiers in biochemical and pharmacological research in depression, pp. 421–437, Raven Press, New York, 1984

    Google Scholar 

  • Post RM, Uhde TW, Ballenger JC, Chatterji DC, Greene RF, et al. Carbamazepine and its 10,11-epoxide metabolite in plasma and CSF. Relationship to antidepressant response. Archives of General Psychiatry 40: 673–676, 1983

    Article  PubMed  CAS  Google Scholar 

  • Pynnönen S, Björkquist S-E, Pekkarinen A. The pharmacokinetics of carbamazepine in alcoholics. In Meinardi et al. (Eds) Advances in epileptology, pp. 285–289, Swets & Zeitlinger, Amsterdam/Lisse, 1978

    Google Scholar 

  • Pynnönen S, Frey H, Sillanpää M. The auto-induction of carbamazepine during long term therapy. International Journal of Clinical Pharmacology, Therapeutics and Toxicology 18: 247–252, 1980

    Google Scholar 

  • Pynnönen S, Kanto J, Sillanpä M, Erkkola R. Carbamazepine: placental transport, tissue concentrations in foetus and newborn, and level in milk. Acta Pharmacologica et Toxicologica 41: 244–253, 1977

    Article  PubMed  Google Scholar 

  • Pynnönen S, Sillanpää M. Carbamazepine in mother’s milk. Lancet 2: 563, 1975

    Article  PubMed  Google Scholar 

  • Pynnönen A, Sillanpää M, Frey H, Iisalo E. Carbamazepine and its 10,11-epoxide in children and adults with epilepsy. European Journal of Clinical Pharmacology 11: 129–133, 1977

    Article  PubMed  Google Scholar 

  • Ramsey RE, Wilder BJ, Berger JR, Bruni J. A double-blind study comparing carbamazepine with phenytoin as initial seizure therapy in adults. Neurology 33: 904–910, 1983

    Article  Google Scholar 

  • Rane A, Bertilsson L, Palmer L. Disposition of placentally transferred carbamazepine (Tegretol ®) in the newborn. European Journal of Clinical Pharmacology. 8: 283–284, 1975

    Article  PubMed  CAS  Google Scholar 

  • Rane A, Höjer B, Wilson JT. Kinetics of carbamazepine and its 10,11-epoxide metabolite in children. Clinical Pharmacology and Therapeutics 19: 276–283, 1976

    PubMed  CAS  Google Scholar 

  • Rapeport WG. Factors influencing the relationship between carbamazepine plasma concentration and its clinical effects in patients with epilepsy. Clinical Neuropharmacology 8: 141–149, 1985

    Article  PubMed  CAS  Google Scholar 

  • Rey E, D’Athis P, deLauture D, Dulac O, Aicardi J, et al. Pharmacokinetics of carbamazepine in the neonate and in the child. International Journal of Clinical Pharmacology and Biopharmacology 17: 90–96, 1979

    CAS  Google Scholar 

  • Richens A, Dunlop F. Serum-phenytoin levels in the management of epilepsy. Lancet 2: 247–248, 1975

    Article  PubMed  CAS  Google Scholar 

  • Ritola E, Malinen L. A double-blind comparison of carbamazepine and clomethiazole in the treatment of alcohol withdrawal syndrome. Acta Psychiatrica Scandinavica 64: 254–259, 1981

    Article  PubMed  CAS  Google Scholar 

  • Riva R, Albani F, Ambrossetto G, Contin M, Cortelli P, et al. Diurnal fluctuations in free and total steady-state plasma levels of carbamazepine and correlation with intermittent side effects. Epilepsia 25: 476–481, 1984

    Article  PubMed  CAS  Google Scholar 

  • Sato H, Doi M, Okuno T. Carbamazepine as a sole anticonvulsant for partial seizures. Brain and Development 2: 97–102, 1979

    Article  Google Scholar 

  • Schmidt D, Cornaggia C, Fabian A. Carbamazepine suspension for acute treatment of trigeminal neuralgia: clinical effects in relation to plasma concentration. In Levy et al. (Eds) Metabolism of antiepileptic drugs, pp. 35–42, Raven Press, New York, 1984

    Google Scholar 

  • Schmidt D, Haenel F. Therapeutic plasma levels of phenytoin, phenobarbital, and carbamazepine: individual variation in relation to seizure frequency and type. Neurology 34: 1252–1255, 1984

    Article  PubMed  CAS  Google Scholar 

  • Schneider H, Berenguer J. CSF and plasma concentrations of carbamazepine and some metabolites in steady state. In Gardner-Thorpe et al. (Eds) Antiepileptic drug monitoring, pp. 264–273, Pitman Press, Avon, 1977

    Google Scholar 

  • Schneider H, Stenzel E. Carbamazepin: Tageszeitlicher Verlauf des Serumspiegais unter Langzeitmedikation. Antiepileptische Langzeitmedikation, Bibliotheca Psychiatrica 151: 32–42, 1975

    Google Scholar 

  • Schoeman JF, Elyas AA, Brett EM, Lascelles PT. Altered ratio of carbamazepine-10,11-epoxide/carbamazepine in plasma of children: evidence of anticonvulsant drug interaction. Developmental Medicine and Child Neurology 26: 749–755, 1984a

    Article  PubMed  CAS  Google Scholar 

  • Schoeman JF, Elyas AA, Brett EM, Lascelles PT. Correlation between plasma carbamazepine-10,11-epoxide concentration and drug side-effects in children with epilepsy. Developmental Medicine and Child Neurology 26: 756–764, 1984b

    Article  PubMed  CAS  Google Scholar 

  • Shorvon SD, Galbraith AW, Laundy M, Vydelingum L, Reynolds EH. Monotherapy for epilepsy. In Johannessen et al. (Eds) Antiepileptic therapy: advances in drug monitoring, pp. 213–220, Raven Press, New York, 1980

    Google Scholar 

  • Sillanpää M, Pynnönen S, Laippala P, Säkö E. Carbamazepine in the treatment of partial epileptic seizures in infants and young children. a preliminary study. Epilepsia 20: 563–569, 1979

    Article  PubMed  Google Scholar 

  • Simonsen N, Zander Olsen P, Kühl V, Lund M, Wendelboe J. A comparative controlled study between carbamazepine and diphenylhydantoin in psychomotor epilepsy. Epilepsia 17: 169–176, 1976

    Article  PubMed  CAS  Google Scholar 

  • Sonne J, Lühdorf K, Larsen NE, Andreasen PB. Lack of interaction between cimetidine and carbamazepine. Acta Neurologica Scandinavica 68: 253–256, 1983

    Article  PubMed  CAS  Google Scholar 

  • Strandjord RE, Johannessen SI. Single-drug therapy with carbamazepine in patients with epilepsy: serum levels and clinical effect. Epilepsia 21: 655–662, 1980

    Article  PubMed  CAS  Google Scholar 

  • Tomson T. Inderdosage fluctuations in plasma carbamazepine concentration determine intermittent side effects. Archives of Neurology 41: 830–834, 1984

    Article  PubMed  CAS  Google Scholar 

  • Tomson T, Bertilsson L. Potent therapeutic effect of carbamazepine-10,11-epoxide in trigeminal neuralgia. Archives of Neurology 41: 598–601, 1984

    Article  PubMed  CAS  Google Scholar 

  • Tomson T, Ekbom K. Trigeminal neuralgia: time course of pain in relation to carbamazepine dosing. Cephalalgia 1: 91–97, 1981

    Article  PubMed  CAS  Google Scholar 

  • Tomson T, Tybring G, Bertilsson L. Single dose kinetics and metabolism of carbamazepine-10,11-epoxide. Clinical Pharmacology and Therapeutics 33: 58–65, 1983

    Article  PubMed  CAS  Google Scholar 

  • Tomson T, Tybring G, Bertilsson L, Ekbom K, Rane A. Carbamazepine therapy in trigeminal neuralgia. Clinical effects in relation to plasma concentration. Archives of Neurology 37: 699–703, 1980

    Article  PubMed  CAS  Google Scholar 

  • Troupin A, Moretti Ojemann L, Halpern L, Dodrill C, Wilkus R, et al. Carbamazepine — a double-blind comparison with phenytoin. Neurology 27: 511–519, 1977

    Article  PubMed  CAS  Google Scholar 

  • Tybring G, von Bahr C, Bertilsson L, Collste H, Glaumann H, et al. Metabolism of carbamazepine and its epoxide metabolite in human and rat liver in vitro. Drug Metabolism and Disposition 9: 561–564, 1981

    PubMed  CAS  Google Scholar 

  • Valsalan VC, Cooper GL. Carbamazepine intoxication caused by interaction with isoniazid. British Medical Journal 285: 261–262, 1982

    Article  PubMed  CAS  Google Scholar 

  • Warren JW, Benmaman JD, Braxton B, Wannamaker BB, Levy RH. Kinetics of a carbamazepine-ethosuximide interaction. Clinical Pharmacology and Therapeutics 28: 646–651, 1980

    Article  PubMed  CAS  Google Scholar 

  • Wedlund PJ, Patel IH, Levy RH. Induction effect of phenobarbital on carbamazepine-10,11-epoxide kinetics in the rhesus monkey. Journal of Pharmacokinetics and Biopharmacy 10: 427–435, 1982

    CAS  Google Scholar 

  • Wheeler SD, Ramsay RE, Weiss J. Drug-induced down-beat nystagmus. Annals of Neurology 12: 227–228, 1982

    Article  PubMed  CAS  Google Scholar 

  • Wright JM, Stokes EF, Sweeney VP. Isoniazid-induced carbamazepine toxicity and vice versa. New England Journal of Medicine 307: 1325–1327, 1982

    Article  PubMed  CAS  Google Scholar 

  • Yerby MS, Friel PN, Miller DQ. Carbamazepine protein binding and disposition in pregnancy. Therapeutic Drug Monitoring 7: 269–273, 1985

    Article  PubMed  CAS  Google Scholar 

  • Zielinski JJ, Haidukewych D, Leheta BJ. Carbamazepine-phenytoin interaction: elevation of plasma phenytoin concentrations due to carbamazepine comedication. Therapeutic Drug Monitoring 7: 51–53, 1985

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Karolinska Institute, Huddinge Hospital, S-141 86, Huddinge, Sweden

    Leif Bertilsson & Torbjörn Tomson

  2. Department of Neurology, Karolinska Institute, Söder Hospital, Stockholm, Sweden

    Leif Bertilsson & Torbjörn Tomson

Authors
  1. Leif Bertilsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Torbjörn Tomson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bertilsson, L., Tomson, T. Clinical Pharmacokinetics and Pharmacological Effects of Carbamazepine and Carbamazepine-10,11-Epoxide. Clin-Pharmacokinet 11, 177–198 (1986). https://doi.org/10.2165/00003088-198611030-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-198611030-00001

Keywords

Search

Navigation