Journal of Neurology

, Volume 264, Issue 8, pp 1617–1621 | Cite as

Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action

  • Jan M. Keppel Hesselink
  • David J. KopskyEmail author


In 1908 phenytoin (5,5-diphenylhydantoin) was first synthesized as a barbiturate derivative in Germany by professor Heinrich Biltz (1865–1943) and subsequently resynthesized by an American chemist of the pharmaceutical company Parke-Davis in 1923 in Detroit. Screening phenytoin did not reveal comparable sedative side effects as barbiturates and, thus, Parke-Davis discarded this compound as a useful drug. In 1936, phenytoin’s anticonvulsive properties were identified via a new animal model for convulsive disorders, developed by Putnam and Merritt, who also evaluated its clinical value in a number of patients in the period 1937–1940. For many diseases, mechanism of action of phenytoin remains obscure. The voltage-gated sodium channel was and is generally regarded as the main target to explain phenytoin’s activity as an anticonvulsant and an anti-arrhythmic drug. This target, however, does not explain many of the other clinical properties of phenytoin. We will explore a number of original articles on phenytoin published in its 80 years history and give extra attention to the various hypothesis and experiments done to elucidate its mechanisms of action. Phenytoin has been explored in over 100 different disorders; the last two promising indications tested in the clinic are breast cancer and optic neuritis. Most probably, there are multiple targets active for these various disorders, and the insight into which targets are relevant is still very incomplete. It is remarkable that many pharmacological studies tested one dose only, mostly 50 or 100 μM, doses which most probably are higher than the non-plasma bound phenytoin plasma levels obtained during treatment.


Neuropathic pain Phenytoin History Mechanism of action Sodium channels 


Compliance with ethical standards

Conflicts of interest

The authors are holders of two patents: Topical phenytoin for use in the treatment of peripheral neuropathic pain and topical pharmaceutical composition containing phenytoin and a (co-)analgesic for the treatment of chronic pain.


  1. 1.
    Anderson RJ, Development TLCTCHPCDDa (2009) The little compound that could: how phenytoin changed drug discovery and development. Mol Interv 9:208–214CrossRefPubMedGoogle Scholar
  2. 2.
    Putnam TJ, Merritt HH (1937) Experimental determination of the anticonvulsant properties of some phenyl derivatives. Science 85(2213):525–526. doi: 10.1126/science.85.2213.525 CrossRefPubMedGoogle Scholar
  3. 3.
    Friedlander WJ (1986) Putnam, Merritt, and the discovery of Dilantin. Epilepsia 27(3):S1–20CrossRefPubMedGoogle Scholar
  4. 4.
    Yang M, Kozminski DJ, Wold LA, Modak R, Calhoun JD, Isom LL, Brackenbury WJ (2012) Therapeutic potential for phenytoin: targeting Na(v)1.5 sodium channels to reduce migration and invasion in metastatic breast cancer. Breast Cancer Res Treat 134(2):603–615. doi: 10.1007/s10549-012-2102-9
  5. 5.
    Raftopoulos R, Hickman SJ, Toosy A, Sharrack B, Mallik S, Paling D, Altmann DR, Yiannakas MC, Malladi P, Sheridan R, Sarrigiannis PG, Hoggard N, Koltzenburg M, Gandini Wheeler-Kingshott CA, Schmierer K, Giovannoni G, Miller DH, Kapoor R (2016) Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol 15(3):259–269. doi: 10.1016/S1474-4422(16)00004-1 CrossRefPubMedGoogle Scholar
  6. 6.
    Wang Y, Ying X, Chen L, Liu Y, Liang J, Xu C, Guo Y, Wang S, Hu W, Du Y, Chen Z (2016) Electroresponsive nanoparticles improve antiseizure effect of phenytoin in generalized tonic-clonic seizures. Neurotherapeutics. doi: 10.1007/s13311-016-0431-9 Google Scholar
  7. 7.
    Shorvon SD (2009) Drug treatment of epilepsy in the century of the ILAE: the first 50 years, 1909–1958. Epilepsia 3:69–92CrossRefGoogle Scholar
  8. 8.
    Hauptmann A (1912) Luminal bei Epilepsie. Münch Med Wochenschr 59:1907–1909Google Scholar
  9. 9.
    Spiegel E, Wycis H (1940) Convulsive reactivity in hypercholesteremia. Confin Neurol 3(1–2):262–265CrossRefGoogle Scholar
  10. 10.
    Aird RB, Gurchot C (1939) Protective effect of cholesterol in experimental epilepsy. Arch Neurol Psychiatry 42(3):491–506CrossRefGoogle Scholar
  11. 11.
    Aird RB (1939) Mode of action of brilliant vital red in epilepsy. Arch Neurol Psychiatry 42(4):700–723CrossRefGoogle Scholar
  12. 12.
    McQuarrie I (1940) The physicochemical approach to the mechanisms of convulsive reactivity. In: Visscher MB (ed) Chemistry and medicine. University of Minnesota Press, Minneapolis, pp 225–250Google Scholar
  13. 13.
    Merritt H, Putnam TJ (1938) Sodium diphenyl hydantoinate in the treatment of convulsive disorders. J Am Med Assoc 111(12):1068–1073. doi: 10.1001/jama.1938.02790380010004 CrossRefGoogle Scholar
  14. 14.
    Merritt H, Putnam TJ (1938) A new series of anticonvulsant drugs tested by experiments on animals. Arch Neurol Psychiatry 39(5):1003–1015. doi: 10.1001/archneurpsyc.1938.02270050129007 CrossRefGoogle Scholar
  15. 15.
    Merritt H, Putnam TJ (1939) Sodium diphenyl hydantoinate in treatment of convulsive seizures: toxic symptoms and their prevention. Arch Neurol Psychiatry 42(6):1053–1058. doi: 10.1001/archneurpsyc.1939.02270240091005 CrossRefGoogle Scholar
  16. 16.
    Putnam TT (1939) USe of sodium diphenyl hydantoinate as anticonvulsant. J Am Med Assoc 112(21):2190. doi: 10.1001/jama.1939.02800210084024 CrossRefGoogle Scholar
  17. 17.
    Merritt H, Putnam TJ (1940) Further experiences with the use of sodium diphenyl hydantoinate in the treatment of convulsive disorders. Am J Psychiatry 96(5):1023–1027. doi: 10.1176/ajp.96.5.1023 CrossRefGoogle Scholar
  18. 18.
    Lennox WG (1938) A new remedy for epilepsy? Lancet 232(6018):1544CrossRefGoogle Scholar
  19. 19.
    Kimball O (1939) The treatment of epilepsy with sodium diphenyl hydantoinate. J Am Med Assoc 112(13):1244–1245. doi: 10.1001/jama.1939.02800130028009 CrossRefGoogle Scholar
  20. 20.
    Bonafede VI, Nathan RE (1940) The treatment of epilepsy with sodium diphenyl hydantoinate. Psychiatr Q 14(3):603–611. doi: 10.1007/bf01573141 CrossRefGoogle Scholar
  21. 21.
    Frankel SI (1940) Dilantin sodium in the treatment of epilepsy. J Am Med Assoc 114(14):1320–1321. doi: 10.1001/jama.1940.02810140020005 CrossRefGoogle Scholar
  22. 22.
    Fetterman JL (1940) Dilantin sodium therapy in epilepsy: report of study in progress. J Am Med Assoc 114(5):396–400. doi: 10.1001/jama.1940.02810050016004 CrossRefGoogle Scholar
  23. 23.
    Robinson LJ, Osgood R (1940) Comparative effects of phenobarbital and dilantin sodium: in the treatment of epilepsy. J Am Med Assoc 114(14):1334–1335. doi: 10.1001/jama.1940.02810140034009 CrossRefGoogle Scholar
  24. 24.
    Blair D (1940) The modern treatment of epilepsy: a critical survey, with special reference to sodium diphenyl hydantoinate and a comparison of its effects with those of other anticonvulsants. Br J Psychiatry 86(364):888–927. doi: 10.1192/bjp.86.364.888 CrossRefGoogle Scholar
  25. 25.
    Williamson BAM (1940) Severe toxic effects of sodium diphenyl hydantoinate in mentally defective epileptics. Br J Psychiatry 86(364):981–987. doi: 10.1192/bjp.86.364.981 CrossRefGoogle Scholar
  26. 26.
    Firmino F, de Almeida AM, e Silva Rde J, Alves Gda S, Grandeiro Dda S, Penna LH (2014) Scientific production on the applicability of phenytoin in wound healing. Rev Esc Enferm USP 48(1):166–173CrossRefPubMedGoogle Scholar
  27. 27.
    Matsuki N, Quandt FN, Ten Eick RE, Yeh JZ (1984) Characterization of the block of sodium channels by phenytoin in mouse neuroblastoma cells. J Pharmacol Exp Ther 228(2):523–530PubMedGoogle Scholar
  28. 28.
    Morello RS, Begenisich T, Yeh JZ (1984) Determination of the active form of phenytoin. J Pharmacol Exp Ther 230(1):156–161PubMedGoogle Scholar
  29. 29.
    Yeh JZ, Quandt FN, Kirsch GE (1981) Comparative studies of phenytoin action on ionic channels in excitable membranes. Fed Proc 40(31):20Google Scholar
  30. 30.
    Rall TW, Schleiffer L (1985) Drugs effective in the treatment of the epilepsies. In: Gilman AG, Goodman LS, Rall TW, Murad F (eds) Goodman & Gilman’s the pharmacological basis of therapeutics, 7th edn. Macmillan, New York, pp 446–472Google Scholar
  31. 31.
    Handzlik J, Maciag D, Kubacka M, Mogilski S, Filipek B, Stadnicka K, Kiec-Kononowicz K (2008) Synthesis, alpha 1-adrenoceptor antagonist activity, and SAR study of novel arylpiperazine derivatives of phenytoin. Bioorg Med Chem 16(11):5982–5998. doi: 10.1016/j.bmc.2008.04.058 CrossRefPubMedGoogle Scholar
  32. 32.
    Fadiel A, Song J, Tivon D, Hamza A, Cardozo T, Naftolin F (2015) Phenytoin is an estrogen receptor alpha-selective modulator that interacts with helix 12. Reprod Sci 22(2):146–155. doi: 10.1177/1933719114549853 CrossRefPubMedGoogle Scholar
  33. 33.
    Patejdl R, Leroux AC, Noack T (2015) Phenytoin inhibits contractions of rat gastrointestinal and portal vein smooth muscle by inhibiting calcium entry. Neurogastroenterol Motil 27(10):1453–1465. doi: 10.1111/nmo.12645 CrossRefPubMedGoogle Scholar
  34. 34.
    Suzuki AM, Yoshimura A, Ozaki Y, Kaneko T, Hara Y (2009) Cyclosporin A and phenytoin modulate inflammatory responses. J Dent Res 88(12):1131–1136. doi: 10.1177/0022034509350566 CrossRefPubMedGoogle Scholar
  35. 35.
    Handzlik J, Szymanska E, Nedza K, Kubacka M, Siwek A, Mogilski S, Filipek B, Kiec-Kononowicz K (2011) Pharmacophore models based studies on the affinity and selectivity toward 5-HT1A with reference to alpha 1-adrenergic receptors among arylpiperazine derivatives of phenytoin. Bioorg Med Chem 19(3):1349–1360. doi: 10.1016/j.bmc.2010.11.051 CrossRefPubMedGoogle Scholar
  36. 36.
    Cobos EJ, Baeyens JM, Del Pozo E (2005) Phenytoin differentially modulates the affinity of agonist and antagonist ligands for sigma 1 receptors of guinea pig brain. Synapse 55(3):192–195. doi: 10.1002/syn.20103 CrossRefPubMedGoogle Scholar
  37. 37.
    Tunnicliff G (1996) Basis of the antiseizure action of phenytoin. Gen Pharmacol 27(7):1091–1097CrossRefPubMedGoogle Scholar
  38. 38.
    Holopainen IE, Kivela R, Korpi ER (2001) Do antiepileptics phenytoin, carbamazepine, and loreclezole show GABA(A) receptor subtype selectivity in rat brain sections? Neurochem Res 26(1):89–94CrossRefPubMedGoogle Scholar
  39. 39.
    Wong PT, Teo WL (1988) Properties of phenytoin binding sites in the rat brain: regional distribution and postnatal development. Jpn J Pharmacol 46(3):261–266CrossRefPubMedGoogle Scholar
  40. 40.
    Eijkelkamp N, Linley JE, Baker MD, Minett MS, Cregg R, Werdehausen R, Rugiero F, Wood JN (2012) Neurological perspectives on voltage-gated sodium channels. Brain 135(Pt 9):2585–2612CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kuo CC (1998) A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. Mol Pharmacol 54(4):712–721PubMedGoogle Scholar
  42. 42.
    Lucas PT, Meadows LS, Nicholls J, Ragsdale DS (2005) An epilepsy mutation in the beta1 subunit of the voltage-gated sodium channel results in reduced channel sensitivity to phenytoin. Epilepsy Res 64(3):77–84. doi: 10.1016/j.eplepsyres.2005.03.003 CrossRefPubMedGoogle Scholar
  43. 43.
    Colombo E, Franceschetti S, Avanzini G, Mantegazza M (2013) Phenytoin inhibits the persistent sodium current in neocortical neurons by modifying its inactivation properties. PLoS One 8(1):e55329. doi: 10.1371/journal.pone.0055329 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Institute for Neuropathic PainBosch en DuinThe Netherlands
  2. 2.Institute for Neuropathic PainAmsterdamThe Netherlands

Personalised recommendations