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Effect of diphenylhydantoin on hepatic drug hydroxylation

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Summary

Two experiments were done on eight males who were to receive diphenylhydantoin (DPH) for epilepsy: the metabolic disposition of phenazone (antipyrine, 14 mg/kg p.o.) was examined before and after 2.5–6 months of treatment with DPH (300 mg/day). The average half-life of phenazone fell from 10.0 h in the first study to 6.1 h after DPH treatment; and the urinary excretion of unchanged phenazone decreased within 24 h from 28.5 mg (2.8% of the dose) to 18.1 mg (1.8% of the dose). Similar results were obtained when data were calculated on the basis of the output of creatinine. The amount of 4-OH-phenazone, the principal hydroxylated metabolite excreted in the urine in the 24 h after dosing, increased from 185 mg (18% of the dose) to 300 mg (29.5% of the dose) during treatment with DPH. In an additional epileptic patient, who suffered from Icterus juvenilis Meulengracht, the half-life of phenazone decreased from 20.7 h to 6.6 h after 22 days treatment with DPH (300 mg/day); the serum bilirubin concentration fell from 2.6 mg% to 1.0 mg% during the same period. The results are considered to show increased activity of hepatic microsomal drug hydroxylating systems, which can be attributed to treatment with DPH for several weeks.

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Reference

  1. Arnold, K., Gerber, N.: The rate of decline of diphenylhydantoin in human plasma. Clin. Pharmacol. Ther.11, 121–134 (1970)

    Google Scholar 

  2. Booker, H.E., Tormey, A., Toussaint, J.: Concurrent administration of phenobarbital and diphenylhydantoin: lack of interference effect. Neurology (Minneap.)21, 383–385 (1971)

    Google Scholar 

  3. Brodie, B.B., Axelrod, J., Soberman, R., Levy, B.B.: The estimation of antipyrine in biological materials. J. biol. Chem.179, 25–29 (1949)

    Google Scholar 

  4. Brooks, S.M., Werk, E.E., Ackermann, S.J., Sullivan, J., Thrasher, K.: Adverse effects of phenobarbital on corticosteroid metabolism in patients with bronchial asthma. New Engl. J. Med.286, 1125–1128 (1972)

    Google Scholar 

  5. Buchanan, R.A., Allen, R.J.: Diphenylhydantoin (Dilantin®) and phenobarbital blood levels in epileptic patients. Neurology (Minneap.)21, 866–871 (1971)

    Google Scholar 

  6. Buchanan, R.A., Kinkel, A.W., Goulet, J.R., Smith, T.C.: The metabolism of diphenylhydantoin (Dilantin®) following once-daily administration. Neurology (Minneap.)22, 126–130 (1972)

    Google Scholar 

  7. Cucinell, S.A., Koster, R., Conney, A.H., Burns, J.J.: Stimulatory effect of phenobarbital on the metabolism of diphenylhydantoin. J. Pharmacol. exp. Ther.141, 157–160 (1963)

    Google Scholar 

  8. Cucinell, S.A., Conney, A.H., Sansur, M., Burns, J.J.: Drug interactions in man. I. Lowering effect of phenobarbital on plasma levels of bishydroxycoumarin (Dicumarol) and diphenylhydantoin (Dilantin®). Clin. Pharmacol. Ther.6, 420–429 (1965)

    Google Scholar 

  9. Eichelbaum, M., Bodem, G., Schneider-Deters, Ch.: Antipyrine half-life, antipyrine metabolism and thyroid function. Arch. Pharmacol.277, R-14 (1973)

    Google Scholar 

  10. Elies, W., Heni, N., Remmer, H.: The effect of some drugs on lipids and drug metabolizing enzymes in experimental fatty liver of the rat. Naunyn-Schmiedeberg's Arch. Pharmak.266, 317 (1970)

    Google Scholar 

  11. Eling, T.E., Harbison, R.D., Becker, B.A., Fouts, J.R.: Diphenylhydantoin effect on neonatal and adult rat hepatic drug metabolism. J. Pharmacol. exp. Ther.171, 127–134 (1970)

    Google Scholar 

  12. Eling, T.E., Harbison, R.D., Becker, B.A., Fouts, J.R.: Kinetic changes in microsomal drug metabolism with age and diphenylhydantoin treatment. Europ. J. Pharmacol.11, 101–108 (1970)

    Google Scholar 

  13. Frey, H.H., Kampmann, E., Nielsen, L.K.: Study on combined treatment with phenobarbital and diphenylhydantoin. Acta pharmacol. (Kbh.)26, 284–292 (1968)

    Google Scholar 

  14. Garrettson, L.K., Dayton, P.G.: Disappearance of phenobarbital and diphenylhydantoin from serum of children. Clin. Pharmacol. Ther.11, 674–679 (1970)

    Google Scholar 

  15. Gerber, N., Arnold, K.: Studies on the metabolism of diphenylhydantoin in mice. J. Pharmacol. exp. Ther.167, 77–90 (1969)

    Google Scholar 

  16. Glazko, A.J., Chang, T., Baukema, J., Dill, W.A., Goulet, J.R., Buchanan, R.A.: Metabolic disposition of diphenylhydantoin in normal human subjects following intravenous administration. Clin. Pharmacol. Ther.10, 498–504 (1969)

    Google Scholar 

  17. Hahn, T.J., Hendin, B.A., Scharp, C.R., Haddad, J.G.: Effect of chronic anticonvulsant therapy on serum 25-HO-calciferol levels in adults. New Engl. J. Med.287, 900–904 (1972)

    Google Scholar 

  18. Halberkann, J., Fretwurst, F.: Die Stoffwechselprodukte des Pyramidons und verwandter Verbindungen beim Menschen. 1. Arch. Inst. Biol. (Sao Paulo)11, 149 (1940) 2. Z. physiol. Chem.285, 97–127 (1950)

    Google Scholar 

  19. Hansen, J.M., Siersbaek-Nielsen, Skovsted, L.: Carbamazepine-induced acceleration of diphenylhydantoin and warfarin metabolism in man. Clin. Pharmacol. Ther.12, 539–543 (1971)

    Google Scholar 

  20. Hansen, H.M., Siersbaek-Nielsen, Kristensen, M., Skovsted, L., Christensen, L.K.: Effect of diphenylhydantoin on the metabolism of dicumarol in man. Acta med. scand.189, 15–19 (1971)

    Google Scholar 

  21. Hirschmann, J.: Die Kontrolle der Diphenylhydantoin-Dosierung bei Anfallsleiden durch Bestimmung der Serumspiegel. Med. Welt20 (N.F.), 705–710 (1969)

    Google Scholar 

  22. Hunter, J., Carrella, M., Maxwell, J.D., Stewart, D.A., Williams, R.: Urinary D-glucaric-acid excretion as a test for hepatic enzyme induction in man. Lancet1971 I, 572–574

    Google Scholar 

  23. Hunter, J., Maxwell, J.D., Stewart, D.A., Parsons, V., Williams, R.: Altered calcium metabolism in epileptic children on anticonvulsants. Brit. med. J.1971 IV, 202–206

    Google Scholar 

  24. Kristensen, M., Hansen, J.M., Skovsted, L.: The influence of phenobarbital on the half-life of diphenylhydantoin in man. Acta med. scand.185, 347–350 (1969)

    Google Scholar 

  25. Kutt, H., Haymes, J., Verebely, K., Mc Dowell, F.: The effect of phenobarbital on plasma diphenylhydantoin level and metabolism in man and in rat liver microsomes. Neurology (Minneap.)19, 611–616 (1969)

    Google Scholar 

  26. Livingstone, S., Berman, W., Pauli, L.L.: Anticonvulsant drugs and vitamine D-metabolism. J. Amer. med. Ass.22, 1634–1635 (1973)

    Google Scholar 

  27. Lücking, Th., Delling, G.: Schwere rachitische Osteopathie bei antiepileptischer Langzeitbehandlung. Dtsch. med. Wschr.98, 1036–1040 (1973)

    Google Scholar 

  28. Mac Donald, M.G., Robinson, D.S., Sylvester, D., Jaffe, J.J.: The effects of phenobarbital, chloral betaine and glutethimide administration on warfarin plasma levels and hypoprothrombinemic responses in man. Clin. Pharmacol. Ther.10, 81–84 (1969)

    Google Scholar 

  29. O'Malley, K., Crooks, J., Duke, E., Stevenson, I.H.: Effect of age and sex on human drug metabolism. Brit. med. J.1971 III, 607–609

    Google Scholar 

  30. Remmer, H., Hirschmann, J., Greiner, I.: Die Bedeutung von Kumulation und Elimination für die Dosierung von Phenytoin (Diphenylhydantoin). Dtsch. med. Wschr.94, 1265–1272 (1969)

    Google Scholar 

  31. Remmer, H.: Induction of drug metabolizing enzyme system in the liver. Europ. J. clin. Pharmacol.5, 116–136 (1972)

    Google Scholar 

  32. Remmer, H., Schoene, B., Fleischmann, R.A.: Induction of the unspecific microsomal hydroxylase in the human liver. Drug Metabol. Disposit.1, 224–229 (1973)

    Google Scholar 

  33. Rizzo, M., Morselli, P.L., Garattini, S.: Further observations on the interactions between phenobarbital and diphenylhydantoin during chronic treatment in the rat. Biochem. Pharmacol.21, 449–454 (1972)

    Google Scholar 

  34. Schaefer, K., Flury, W.H., Herrath, D., Kraft, D., Schweingruber, R.: Vitamin-D-Stoffwechsel und Antiepileptica. Schweiz. med. Wschr.102, 785–791 (1972)

    Google Scholar 

  35. Schüppel, R.: Pharmakokinetische Untersuchungen an der alkoholisierten Ratte. Dissertation, Mathem.-naturwiss. Fakultät Tübingen 1968

  36. Sher, S.P.: Drug enzyme induction and drug interaction: Literature tabulation. Toxicol. appl. Pharmacol.18, 780–834 (1971)

    Google Scholar 

  37. Sotaniemi, E., Arvela, P., Hakkarainen, H., Huhti, E.: The clinical significance of microsomal enzyme induction in the therapy of epileptic patients. Ann. clin. Res.2, 223–227 (1970)

    Google Scholar 

  38. Stevenson, J.H., Browning, M., Crooks, J., O'Malley, K.: Changes in human drug metabolism after long-term exposure to hypnotics. Brit. med. J.1972 IV, 322–324

    Google Scholar 

  39. Svensmark, O., Schiller, P.J., Buchthal, F.: 5,5-Diphenylhydantoin (Dilantin) blood levels after oral or intravenous dosage in man. Acta pharmacol. toxicol.16, 331–346 (1960)

    Google Scholar 

  40. Szeberenyi, S., Tacconi, M.T., Garattini, S.: Increased metabolism of metyrapone in rats pretreated with diphenylhydantoin or phenobarbital. Endocrinology85, 575–576 (1969)

    Google Scholar 

  41. Taussky, H.H.: Creatinine and creatine in urine and serum. In: Standard Methods of Clinical Chemistry, pp. 99–112 (Seligson, D. Ed.) New York: Academic Press 1961

    Google Scholar 

  42. Werk, E.E., Mc Gee, J., Sholiton, L.J.: Effect of diphenylhydantoin on cortisol metabolism in man. J. clin. Invest.43, 1824–1835 (1964)

    Google Scholar 

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Authors and Affiliations

  1. Neurologische Klinik and Institut f. Toxikologie der Univ. Tübingen, Tübingen, Federal Republic of Germany

    F. Petruch, R. V. A. Schüppel & G. Steinhilber

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  1. F. Petruch
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  2. R. V. A. Schüppel
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  3. G. Steinhilber
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Petruch, F., Schüppel, R.V.A. & Steinhilber, G. Effect of diphenylhydantoin on hepatic drug hydroxylation. Eur J Clin Pharmacol 7, 281–285 (1974). https://doi.org/10.1007/BF00560345

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