Bioavailability and pharmacokinetics of phenytoin during pregnancy

Summary

Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration — time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in nonpregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.

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

References

  1. Cranford RE, Leppik IE, Patrick B, Anderson CB, Kostick B (1977) Intravenous phenytoin: clinical and pharmacokinetic aspects. Neurology (Minneapolis) 27: 376

    Google Scholar 

  2. Dam M, Mygind K, Christiansen J (1976) Antiepileptic drugs, plasma clearance during pregnancy. In: Janz D (ed) Epileptology. Thieme, Stuttgart, pp 178–183

    Google Scholar 

  3. Eadie MJ, Lander CM, Tyrer JH (1977) Plasma drug level monitoring in pregnancy. Clin Pharmacokinet 2: 427–436

    CAS  PubMed  Google Scholar 

  4. Forsythe GE, Malcolm MA, Moler CB (1977) Computer models for mathematical computations. Prentice Hall, Englewood Cliffs, NJ, pp 132–147

    Google Scholar 

  5. Guelen PJM (1975) Discussion, In: Schneider H, Janz D, Gardner-Thorpe C, Meinardi K, Sherwin AL (eds) Clinical pharmacology of antiepileptic drugs. Springer, Berlin Heidelberg New York pp 45–46

    Google Scholar 

  6. Gugler R, Manion CV, Azarnoff DL (1976) Phenytoin: pharmacokinetics and bioavailability. Clin Pharmacol Ther 19: 135–142

    CAS  PubMed  Google Scholar 

  7. Hayes MJ, Langman MJS, Short AH (1975) Changes in drug metabolism with increasing age. 2. phenytoin clearance and protein binding. Br J Clin Pharmacol 2: 73–79

    CAS  PubMed  Google Scholar 

  8. Jusko WJ, Koup JR, Alvan G (1976) Nonlinear assessment of phenytoin bioavailability. J Pharmacokinet Biopharm 4: 327–336

    Article  CAS  PubMed  Google Scholar 

  9. Kochenour NK, Emery MG, Sawchuk RJ (1980) Phenytoin metabolism in pregnancy. Obstet Gynaecol 56: 577–582

    CAS  Google Scholar 

  10. Lander CM, Edwards VE, Eadie MJ, Tyrer JH (1977) Plasma anticonvulsant concentrations during pregnancy. Neurology (Minneapolis) 27: 128–131

    CAS  PubMed  Google Scholar 

  11. Marquardt DM (1963) An algorithm for least-squares estimation of nonlinear parameters. J Soc Ind Appl Math 11: 431–441

    Article  Google Scholar 

  12. Martis L, Levy RH (1973) Bioavailability calculations for drugs showing simultaneous first-order and capacity-limited elimination kinetics. J Pharmacokinet Biopharmaceut 1: 283–294

    CAS  Google Scholar 

  13. Metzler CM, Tong DDM (1981) Computational problems of compartment models with Michaelis-Menten-type elimination. J Pharm Sci 70: 733–737

    CAS  PubMed  Google Scholar 

  14. Mygind KI, Dam M, Christiansen J (1976) Phenytoin and phenobarbitone plasma clearance during pregnancy. Acta Neurologica Scand 54: 160–166

    CAS  Google Scholar 

  15. Philbert A, Dam M (1982) Antiepileptic drug disposition during pregnancy: review of the literature. In: Janz D, Bossi L, Dam M, Helge H, Richens A, Schmidt D (eds) Epilepsy, pregnancy, and the child. Raven Press, New York, pp 109–114

    Google Scholar 

  16. Ramsay RE, Strauss RG, Wilder BJ, Willmore LJ (1978) Status epilepticus in pregnancy. Effect of phenytoin malabsorption on seizure control. Neurology (Minneapolis) 28: 85–89

    CAS  PubMed  Google Scholar 

  17. Smith MT, Smith TC (1981) The unsteady model. An alternative approach to nonlinear pharmacokinetics. Eur J Clin Pharmacol 20: 387–398

    Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lander, C.M., Smith, M.T., Chalk, J.B. et al. Bioavailability and pharmacokinetics of phenytoin during pregnancy. Eur J Clin Pharmacol 27, 105–110 (1984). https://doi.org/10.1007/BF02395215

Download citation

Key words

  • phenytoin
  • epileptic women
  • pharmacokinetics
  • bioavailability
  • pregnancy