Skip to main content
SpringerLink
Log in

Daily Variations in Steady-State Plasma Concentrations of Carbamazepine and its Metabolites in Epileptic Children

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Summary

Total plasma carbamazepine, carbamazepine-10,11-epoxide (CBZ-EP) and 10,11-dihydro-10,11-trans-dihydroxy-carbamazepine (CBZ-DIOL) concentrations were measured during a 24h period in 21 patients receiving carbamazepine monotherapy, in equally divided doses, every 12h. Interdose and diurnal variations in plasma concentrations of parent drug and metabolites were assessed. Carbamazepine and both metabolites showed significant differences in mean 4h post-dose plasma concentrations between day and night dosing (p < 0.001).

Significant linear correlations were obtained between carbamazepine dose and plasma concentrations of carbamazepine, CBZ-EP and CBZ-DIOL when sampling times were standardised (p < 0.01). Comparisons of plasma concentrations of the parent compound with those of its 2 main metabolites revealed significant linear correlations in all cases (p < 0.01). The effects of daily fluctuations in plasma concentrations of all 3 compounds on their relative concentrations (CBZ-EP: carbamazepine, CBZ-DIOL: carbamazepine and CBZ-DIOL: CBZ-EP) during the 24h period were also determined: the plasma concentration ratios CBZ-EP: carbamazepine and CBZ-DIOL: carbamazepine were significantly related to the dose of carbamazepine at fixed sampling times (p < 0.05, with 1 exception). The large interdose and diurnal variation in plasma carbamazepine concentrations observed in this study (approximately 40% decrease from peak to trough) has important implications both clinically and in relation to therapeutic drug monitoring.

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

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

    Article  PubMed  CAS  Google Scholar 

  • Bertilsson L, Tomson T. Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide: an update. Clinical Pharmacokinetics 11: 177–198, 1986

    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, 1984

    Article  PubMed  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 

  • Cereghino JJ, van Meter JC, Brock JT, Penry JK, Smith LD, et al. Preliminary observations of serum carbamazepine concentration in epileptic patients. Neurology 23: 357–366, 1973

    Article  PubMed  CAS  Google Scholar 

  • Diehl LW, Muller-Oerlinghausen B, Riedel E. The importance of individual pharmacokinetic data for treatment of epilepsy with carbamazepine. International Journal of Clinical Pharmacology 14: 144–148, 1976

    CAS  Google Scholar 

  • Eichelbaum M, Bertilsson L, Lund L, Sjoqvist F. Plasma levels of carbamazepine and carbamazepine-10,11-epoxide during carbamazepine therapy in epileptic patients. European Journal of Clinical Pharmacology 9: 417–421, 1976

    Article  CAS  Google Scholar 

  • Elyas AA, Patsalos PN, Agbato OA, Brett EM, Lascelles PT. Factors influencing simultaneous concentrations of total and free carbamazepine and carbamazepine-10,11-epoxide in serum of children with epilepsy. Therapeutic Drug Monitoring 8: 288–292, 1986

    Article  PubMed  CAS  Google Scholar 

  • Forsythe WI, Prendergast MP, Toothill C, Broughton PMG. Carbamazepine serum levels in children with epilepsy: a micro immuno-assay technique. Developmental Medicine and Child Neurology 21: 441–447, 1979

    Article  PubMed  CAS  Google Scholar 

  • Forsythe WI, Sills MA. One drug for childhood grand mal: medical audit for three-year remissions. Developmental Medicine and Child Neurology 26: 742–748, 1984

    Article  PubMed  CAS  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 

  • Hartley R, Lucock M, Forsythe WI, Smithells RW. Solid-phase extraction of carbamazepine and two major metabolites from plasma for analysis by HPLC. Journal of Liquid Chromatography 10: 2393–2409, 1987

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Hundt HKL, Aucamp AK, Muller FO, Potgieter MA. Carbamazepine and its major metabolites in plasma: a summary of eight years of therapeutic drug monitoring. Therapeutic Drug Monitoring 5: 427–435, 1983

    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. 110–126, Pitman Medical, Tunbridge Wells, 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 

  • Macphee GJA, Butler E, Brodie MJ. Intradose and circadian variation in circulating carbamazepine and its epoxide in epileptic patients: a consequence of autoinduction of metabolism. Epilepsia 28: 286–294, 1987

    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 

  • 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 

  • 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 

  • Pynnonen S, Sillanpaa M, Frey H, Iisalo E. Carbamazepine and its 10,11-epoxide in children and adults with epilepsy. European Journal of Clinical Pharmacology 11: 129–132, 1977

    Article  PubMed  CAS  Google Scholar 

  • 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. Therapeutic Drug Monitoring 9: 298–303, 1987

    Article  PubMed  CAS  Google Scholar 

  • Rane A, Hojer 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 

  • Riva R, Albani F, Ambrosette 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 

  • Rylance GW, Butcher GM, Moreland T. Saliva carbamazepine levels in children. British Medical Journal 2: 1481, 1977

    Article  PubMed  CAS  Google Scholar 

  • Rylance GW, Edwards C, Gard PR. Carbamazepine-10,11-epoxide in children. British Journal of Clinical Pharmacology 18: 935–939, 1985

    Article  Google Scholar 

  • Rylance GW, Moreland TA, Butcher GM. Carbamazepine dose-frequency requirement in children. Archives of Disease in Childhood 54: 454–458, 1979

    Article  PubMed  CAS  Google Scholar 

  • Sillanpaa M. Carbamazepine, pharmacology and clinical uses. Acta Neurologica Scandinavica 64 (Suppl. 88): 15–31, 1981

    Google Scholar 

  • Strandjord RE, Johannessen SI. A preliminary study of serum carbamazepine levels in healthy subjects and in patients with epilepsy. In Schneider et al. (Eds) Clinical pharmacology of anti-epileptic drugs, pp. 181–188, Springer-Verlag, Berlin, 1975

    Chapter  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Tedeschi G, Cenraud B, Guyot M, Gomeni R, Morselli PL, et al. Influence of food on carbamazepine absorption. In Dam et al. (Eds) Advances in epileptology. XIIth Epilepsy International Symposium, pp. 563–567, Raven Press, New York, 1981

    Google Scholar 

  • Tomlin PI, McKinlay I, Smith J. A study on carbamazepine levels, including estimation of 10,11-epoxy-carbamazepine and levels in free plasma and saliva. Developmental Medicine and Child Neurology 28: 713–718, 1986

    Article  PubMed  CAS  Google Scholar 

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

    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 

Download references

Author information

Authors and Affiliations

  1. Paediatric Research Unit, University Department of Paediatrics and Child Health, Leeds, England

    Ronald Hartley, W. Ian Forsythe, Bruce McLain, Pak C. Ng & Mark D. Lucock

Authors
  1. Ronald Hartley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Ian Forsythe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruce McLain
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pak C. Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark D. Lucock
    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

Hartley, R., Forsythe, W.I., McLain, B. et al. Daily Variations in Steady-State Plasma Concentrations of Carbamazepine and its Metabolites in Epileptic Children. Clin. Pharmacokinet. 20, 237–246 (1991). https://doi.org/10.2165/00003088-199120030-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-199120030-00005

Keywords

Search

Navigation