Circadian effect on carbamazepine kinetics in rat

  • B. Bruguerolle
  • M. Valli
  • L. Bouyard
  • G. Jadot
  • P. Bouyard


The purpose of the present study was to investigate whether the time of day (24 h) at which carbamazepine is administered influences its pharmacokinetics in the rat. The pharmacokinetics of a single, 100−1 bodyweightper os, dose of carbamazepine were studied at four different fixed time points of a 24-hour period (i.e. 10.00, 16.00, 22.00 or 04.00 h) in Wistar AF-SPF adult male rats maintained under controled environmental conditions (LD: 18.00 – 06.00h) during October 1978. The total plasma levels and the unbound fraction were measured according to an immunoenzymatic method (EMIT). The effects of fasting were also investigated.

The data shows circadian variations of pharmacokinetic parameters: the maximum peak concentration and the maximum time to reach this peak was observed when the drug was given respectively at 16.00h and at 10.00h. The elimination half-life varied from 15.15 hours at I6.00h to 10.48 hours at 22.00h. The observed variations may be related to: daily fluctuations of absorption or binding of the drug; diurnal variations of the hepatic drug metabolizing enzymes responsible for the inactivation; and/or diurnal variations in excretion rate of the drug.

Key words

Carbamazepine Circadian rhythms Chronopharmacokinetics Rat 


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  1. 1.
    Aymard N. and Soulairac A. (1979) — Chronobiologic changes in pharmacokinetics of dipotassic chlorazepate. 7 th int. Congr. Pharmacol., Symposium on Chronopharmacology, Paris-Velizy 22–24 july 1978, in Remberg A. and Halberg F. Eds.Chronopharmacology, Pergamon Press, Oxford-New York, pp 111–116.Google Scholar
  2. 2.
    Bouyard P., Bruguerolle B., Jadot G., Mesdjian E. and Valli M. (1974) — Mise en évidence d’un rythme nycthéméral dans le phénomène de la curarisation chez le rat.C.R. Soc. Biol., 168: 1005–1007.Google Scholar
  3. 3.
    Bruguerolle B., Mesdjian E., Valli M., Jadot G., Agopian B. and Bouyard P. (1977) — Etude chronopharmacologique du bromure de pancuronium chez le rat.J. Pharmacol. (Paris), 8: 49–58.Google Scholar
  4. 4.
    Bruguerolle B., Mesdjian E., Valli M., Blanc M.C., Jadot G., Vignon E. and Bouyard P. (1978) — Etude chronopharmacologique de l’alfatésine chez le rat mâle.J. Pharmacol. (Paris), 9: 53–64.Google Scholar
  5. 5.
    Bruguerolle B., Valli M., Rakoto J.C., Jadot G., Bouyard P. and Reinberg A. (1979) — Chronopharmacology of pancuronium in the rat: anaesthesia or sea sonal influence? 7 th int. Congr. Pharmacol. Symposium on Chronopharmacology, Paris-Vélizy 22–24 July 1978 in Reinberg A. and Halberg F. Eds., Chronopharmacology, Pergamon Press Oxford-New York, pp 117–123.Google Scholar
  6. 6.
    Carosella L., Di Nardo P., Bernabei R., Cocchi A., Di Gennaro M. and Carbonin P. (1979) — Chronopharmacokinetics of digitalis. Circadian variations of methyldigoxin serum levels after oral administration. 7 th int. Congr. Pharmacol., Symposium on Chronopharmacology, Paris-Vélizy 22–24 July 1978, in Reinberg A. and Halberg F. Eds.,Chronopharmacology, Pergamon Press Oxford-New York. pp 125–134.Google Scholar
  7. 7.
    Clench J., Reinberg A., Chata J. and Dupont J. (1975) — Chronopharmacokinetics of indomethacin in healthy young human subjects.Chronobiologia, 2: 14–15.Google Scholar
  8. 8.
    Cotter L.M., Eadie J.M., Hooper W.D., Lander C.M., Smith G.A. and Tyrer J.H. (1977) — The pharmacokinetics of carbamazepine.Europ. J. Clin. Pharmacol., 12: 451–456.CrossRefGoogle Scholar
  9. 9.
    Gibaldi M. and Perrier D. (1975) — Pharmacokinetics. Dekker Ed., New York.Google Scholar
  10. 10.
    Hardeland R., Hohmann D. and Rensig L. (1973) — The rhythmic organization of rodent liver: a review.J. Interdiscipl. Cycle Res., 4: 89–118.Google Scholar
  11. 11.
    Jori A., Salle D. and Santini V. (197!) — Daily rhythmic variation and liver drug metabolism in rats.Biochem. Pharmacol., 20: 2965–2969.CrossRefPubMedGoogle Scholar
  12. 12.
    Levy R.H. Pitlick W.H., Troupin A.S., Green J.M. and Neal J.M. (1975) Pharmacokinetic eraluation of carbanarepine in normal human volonters. Epilepsia, A6: 197–207.Google Scholar
  13. 13.
    Lockard J.S., Levy R.H., Du Charme L.L., Gongdon W.C. and Patel I.H. (1979) — Carbamazepine revisited in a monkey model.Epilepsia, 20: 169–173.CrossRefPubMedGoogle Scholar
  14. 14.
    Markiewicz A., Semenowicz K., Korczynska J. and Czachowska A. (1979) — Chronopharmacokinetics of dipyridamole.Intern. J. Clin. Pharmacol. Biopharm. 17: 222–224.Google Scholar
  15. 15.
    Meinardi H. (1975) — Carbamazepine. In Woodbury D.M. et al. Eds.,Antiepileptic drugs. Raven Press, New York, pp 487–496.Google Scholar
  16. 16.
    Morselli P.L. (1975) — Carbamazepine: absorption, distribution and excretion. In Penry J.K. and Daly D.D. Eds.,Advances in Neurology: 11, Raven Press, New York, pp 279–293.Google Scholar
  17. 17.
    Morselli P.L., Biandrate P., Frigerio A. and Garattini S. (1972) — Pharmacokinetics of carbamazepine in rats and humans.Europ. J. Clin. Invest., 2: 297–306.Google Scholar
  18. 18.
    Morselli P.L., Gerna M. and Garanttini S. (1971) — Carbamazepine plasma and tissue levels in the rat.Biochem. Pharmacol., 20: 2043–2047.CrossRefPubMedGoogle Scholar
  19. 19.
    Moore-Ede M.C. (1973) — Circadian rhythms of drug effectivness and toxicity.Clin. Pharmacol. Therap., 14: 925–935.Google Scholar
  20. 20.
    Nair V. and Casper R. (1969) — The influence of light on daily rhythm in the hepatic drug-metabolizing enzymes in rat.Life Sciences, 8: 1291–1298.CrossRefPubMedGoogle Scholar
  21. 21.
    Peret J., Chanez M. and Pascal G. (1976) — Taux de protéines dans la ration alimentaire et variations circadiennes des activités enzymatiques impliquées dans le métabolisme des glucides et dans la lipogénèse chez le rat mâle.J. Physiol. (Paris), 72: 683–696.Google Scholar
  22. 22.
    Pynnonen S. (1977) — The pharmacokinetics of carbamazepine in plasma and saliva in man.Acta Pharmacol. Toxicol., 41: 465–471.Google Scholar
  23. 23.
    Razialowski F.M. and Bousquet W.F. (1968) — Daily rhythmic variation in hepatic drug metabolism in the rat and mouse.J. Pharmacol, exptl. Therap., 163: 229–238.Google Scholar
  24. 24.
    Reinberg A. and Halberg F. (1971) — Circadian pharmacology.Ann. Rev. Pharmacol., 11: 455–492.CrossRefPubMedGoogle Scholar
  25. 25.
    Reinberg A., Clench J., Aymard N., Galliot M., Bourdon R., Gervais P., Abulker C. and Dupont J. (1975) — Variations circadiennes des effets de l’éthanol et de Péthanolémie chez l’homme sain. Etude chronopharmacologique.J. Physiol. (Paris), 70: 435–456.Google Scholar
  26. 26.
    Reinberg A., Clench J., Ghata J., Halberg F., Abulker C., Dupont J. and Zagulla-Mally Z. ( 1975) — Rythmes circadiens des paramètres de l’excrétion urinaire du salicylate (chronopharmacocinétique) chez l’homme adulte sain.CR. Ac. Sei. Paris, 280: 1697–1699.Google Scholar
  27. 27.
    Richter K. and Terhaag B. (1978) — The relative bioavaibility and pharmacokinetics of carbamazepine.Intern. J. Clin. Pharmacol., Biopharm., 16: 377–379.Google Scholar
  28. 28.
    Scheving L.E., Pauly S.E. and Hutsai T. (1968) — Circadian fluctuation in plasma proteins of the rat.Am. J. Physiol., 215: 1096–1101.PubMedGoogle Scholar
  29. 29.
    Scheving L.E., Mayersbach H. (von) and Pauly J.E. (1974) — An overview of chronopharmacology.Europ. J. Toxicol., 7: 203–227.Google Scholar
  30. 30.
    Shively C.A. and Vesell E.S. (1975) — Temporal variations in acetaminophen and phenacetin half-life in man.Clin. Pharmacol. Therap., 18: 413–424.Google Scholar
  31. 31.
    Strandjord R.E. and Johannessen S.I. (1975) — A preliminary study of serum carbamazepine levels in healthy subjects and in patients with epilepsy. In Schneider H. et al. (Eds.),Clinical Pharmacology of antiepileptic Drugs, Springer Verlag, Berlin-Heidelberg, pp 181–188.Google Scholar
  32. 32.
    Sturtevant F.M., Sturtevant R.P., Scheving L.E. and Pauly J.E. (1975) — Chronopharmacokinetics of ethanol in man.Chronobiologia, 2, supplt 1, 69.Google Scholar
  33. 33.
    Tredger J.M. and Chabra R.S. (1977) — Circadian variations in microsomal drug metabolizing enzyme activities in rat and rabbit tissues.Xenobiotica, 7: 481–489.CrossRefPubMedGoogle Scholar
  34. 34.
    Valli M., Jadot G., Bruguerolle B., Bussiere H. and Bouyard P. (1979) — Variations circadiennes des protéines plasmatiques chez le rat mâle adulte en synchronisation naturelle.J Physiol. (Paris), 75: 811–814.Google Scholar
  35. 35.
    Vesell E.S., Shively C.A. and Passananti G.T. (1977) — Temporal variations of antipyrine half-life in man.Clin. Pharmacol. Therap., 22: 843–852.Google Scholar

Copyright information

© Springer-Verlag 1981

Authors and Affiliations

  • B. Bruguerolle
    • 1
  • M. Valli
    • 1
  • L. Bouyard
    • 1
  • G. Jadot
    • 1
  • P. Bouyard
    • 1
  1. 1.Laboratory of Medical PharmacologyUniversity of Aix-Marseille IIMarseille Cedex 5France

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