Comparative studies on the distribution and metabolic fate of diphenylhydantoin and 3-ethoxycarbonyldiphenylhydantoin (P-6127) after chronic administrations to dogs and cats

  • Keiji Nakamura
  • Yoshinobu Masuda
  • Katsuyoshi Nakatsuji
  • Tetsuo Hiroka


The oral administration of 100 mg/kg/day of DPH or P-6127 to dogs and cats for more than 1 year resulted in preferential accumulations of the drugs in the superior and inferior colliculus, amygdala, and hippocampus compared to 16 other cerebral areas examined without any manifestation of neurotoxicity. The relative brain to blood levels of DPH in the animals were higher than those of epileptic patients on a maintenance dose.

Both drugs were found concentrated in the pituitary and adrenal; P-6127 less so than DPH. This may be the cause of the infrequent gingival hyperplasia or hirsutism.

DPH was metabolized to the pharmacologically inactive HPPH and a trace of inactive DPHA was found in the chronically treated animals. The ethoxycarbonyl group of P-6127 was split off to form DPH.

The brain/blood and brain/cerebrospinal fluid concentration ratios were higher for P-6127 than for DPH. This may explain the greater anticonvulsant activity of P-6127 in the animals.


Oral Administration Diphenylhydantoin Blood Level Concentration Ratio Maintenance Dose 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bernheim, F.: The hydrolysis of hydantoin by various tissues. Fed. Proc. 6, 238–239 (1947).Google Scholar
  2. ——, and M. L. C. Bernheim: The specificity of hydantoinase. J. biol. Chem. 163, 683–685 (1946).Google Scholar
  3. Butler, T. C.: The metabolic conversion of 5,5-diphenylhydantoin to 5-(p-hydroxyphenyl)-5-phenyl hydantoin. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 119, 1–11 (1957).Google Scholar
  4. ——, and W. J. Waddell: The metabolic fate of 5-ethyl-1-methyl-5-phenyl hydantoin (1-methylnirvanol) and that of 3,5-diethyl-5-phenyl hydantoin (3-ethylnirvanol). Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 127, 171–174 (1959).Google Scholar
  5. Dill, W. A., A. Kazenko, L. M. Wolf, and A. J. Glazko: Studies on 5,5-diphenylhydantoin (Dilantin) in animals and man. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 118, 270–279 (1956).Google Scholar
  6. Gorvin, J. H., and G. Brownlee: Metabolism of 5,5-diphenylhydantoin in the rabbit. Nature (Lond.) 179, 1248 (1957).Google Scholar
  7. Jasper, H. H., and C. Ajmone-Marsan: A stereotaxic atlas of the diencephalon of the cat. Ottawa: National Research Council of Canada 1954.Google Scholar
  8. Kozelka, F., and C. H. Hine: Degradation products of Dilantin. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 77, 175–179 (1943).Google Scholar
  9. Kishi, Y., S. Manmaru, S. Fukui, and K. Aoki: Treatment of epilepsy with 3-ethoxycarbonyl-5,5-diphenylhydantoin (P-6127), a new anticonvulsive agent. Brain and Nerve 16, 982–993 (1964).Google Scholar
  10. Krieger, D. T.: Effect of diphenylhydantoin on pituitaryadrenal interrelations. J. clin. Endocr. 22, 490–493 (1962).Google Scholar
  11. Kutt, H., W. Winters, R. Kokenge, and F. McDowell: Diphenylhydantoin metabolism, blood levels, and toxicity. Arch. Neurol. (Chic.) 11, 642–648 (1964).Google Scholar
  12. Lim, R. K. S., and C. Liu: A stereotaxic atlas of the dog's brain. Springfield, Ill.: Ch. C. Thomas 1960.Google Scholar
  13. Loeser, E. W., jr.: Studies on the metabolism of diphenylhydantoin (Dilantin). Neurology (Minneap.) 11, 424–429 (1961).Google Scholar
  14. Maynert, E. W.: The metabolic fate of diphenylhydantoin in the dog, rat, and man. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 130, 275–284 (1960).Google Scholar
  15. Merrit, H. H., and T. J. Putnam: Sodium diphenyl hydantoinate in the treatment of convulsive disorders. J. Amer. med. Ass. 111, 1068–1073 (1938).Google Scholar
  16. Nakamura, K., K. O'Hashi, K. Nakatsuji, T. Hirooka, K. Fujimoto, and S. Ose: The anticonvulsant activity of 3-ethoxycarbonyl-5,5-diphenylhydantoin (P-6127) in animals. Arch. int. Pharmacodyn. 156, 261–270 (1965).Google Scholar
  17. ——, and M. Kurebe: Differential effects of antiepileptics on hippocampal and pallidal afterdischarges in cats. Jap. J. Pharmacol. 12, 180–190 (1962).Google Scholar
  18. --, and Y. Masuda: Effects of 5,5-diphenylhydantoin and 3-ethoxycarbonyl-5,5-diphenylhydantoin (P-6127) on the dermal and gingival tissues of the experimental animals. Arch. int. Pharmacodyn. (in press) (1966).Google Scholar
  19. Noach, E. L., D. M. Woodbury, and L. S. Goodman: Studies on the absorption, distribution, fate, and excretion of 4-C14-labelled diphenylhydantoin. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 122, 301–314 (1958).Google Scholar
  20. Quinn, D. L.: Influence of diphenylhydantoin on spontaneous release of ovulating hormone in the adult rat. Proc. Soc. exp. Biol. (N. Y.) 119, 892–985 (1965).Google Scholar
  21. Rosenblum, I., and A. A. Stein: Preferential distribution of diphenylhydantoin in primary human brain tumors. Biochem. Pharmacol. 12, 1453–1454 (1963).Google Scholar
  22. Snider, R. S., and W. T. Niemer: A stereotaxic atlas of the cat brain. Chicago: University of Chicago Press 1961.Google Scholar
  23. Swinyard, E. A., W. C. Brown, and L. S. Goodman: Comparative assays of antiepileptic drugs in mice and rats. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 106, 319–330 (1952).Google Scholar
  24. Taen, S., Y. Goto, K. Sekiba, and S. Arai: On the antiepileptic activities of a new compound, ethoxycarbonyldiphenylhydantoin. Brain and Nerve 16, 977–981 (1964).Google Scholar
  25. Toman, J. E. P., E. A. Swinyard, and L. S. Goodman: Properties of maximal seizures, and their alteration by anticonvulsant drugs and other agents. J. Neurophysiol. 9, 231–239 (1946).Google Scholar
  26. Woodbury, D. M.: Effect of hormones on brain excitability and electrolytes. Recent Advanc. Hormone Res. 10, 65–101 (1954).Google Scholar
  27. —— P. S. Timiras, and A. Vernadakis: Hormone, brain, function and behavior, pp. 27–50. New York: Academic Press 1957.Google Scholar

Copyright information

© Springer-Verlag 1966

Authors and Affiliations

  • Keiji Nakamura
    • 1
  • Yoshinobu Masuda
    • 1
  • Katsuyoshi Nakatsuji
    • 1
  • Tetsuo Hiroka
    • 1
  1. 1.Pharmacological DivisionDainippon Pharmaceutical Co. Research LaboratoriesOsakaJapan

Personalised recommendations