Skip to main content

Advertisement

SpringerLink
Log in

Influence of phenobarbital and diphenylhydantoin on the healing of rickets in the rat

  • Published:
Calcified Tissue Research Aims and scope Submit manuscript

Summary

Male weanling Sprague-Dawley rats were administered phenobarbital or diphenylhydantoin (phenytoin, dilantin, DPH), or a combination of the two drugs, while receiving a high calcium, low phosphorus vitamin D-deficient diet. A Line Test evaluation for calcification of the distal end of the radius was performed to determine the presence of rickets and the healing of the disease. After a period of 16 days, rickets had developed in a uniform manner in all groups regardless of drug treatment. Four I.U. of vitamin D3 were then administered to each animal and they were sacrificed either 3 or 9 days later. Three days after the administration of D3, bone calcification had started in all groups, with the greatest response being observed in the control group. Nine days after D3 administration, bone calcification was clearly impaired in PB and PB-DPH treated animals and slightly impaired in the DPH treated group when compared to controls. Weight gain was also impaired after PB and combined PB-DPH treatments. Based on these observations, it is suggested that anticonvulsant drugs, and in particular PB, inhibit, in a yet undetermined fashion, the normal calcification of the growth cartilage which accompanies a single physiological dose of cholecalciferol in the rat.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ashley, J.J., Levy, G.: Inhibition of diphenylhydantoin elimination by its major metabolite. Res. Comm. Chem. Pathol. Pharmacol.4, 297–306 (1972)

    Google Scholar 

  2. Bellin, S.A., Steenbock, H.: Vitamin D and citraturia. J. Biol. Chem.194, 311–316 (1952)

    PubMed  Google Scholar 

  3. Bhattacharyya, M.H., De Luca, H.F.: Subcellular location of rat liver calciferol-25-hydroxylase. Arch. Biochem. Biophys.160, 58–62 (1974)

    PubMed  Google Scholar 

  4. Borgstedt, A.D., Bryson, M.F., Young, L.W., Forbes, G.B.: Long-term administration of antiepileptic drugs and the development of rickets. J. Pediat81, 9–15 (1972)

    PubMed  Google Scholar 

  5. Christiansen, C., Rødbro, P., Munck, O., Munck, O.: Actions of vitamin D2 and D3 and 25-OHD3 in anticonvulsant osteomalacia. Brit. J. Med. J.2, 363–365 (1975)

    Google Scholar 

  6. Conney, A.H., Davison, C., Gastel, R., Burns, J.J.: Adaptive increases in drug-metabolizing enzymes induced by phenobarbital and other drugs. J. Pharmacol. Exp. Ther.130, 1–8 (1960)

    PubMed  Google Scholar 

  7. Corradino, R.A.: Diphenylhydantoin: Direct inhibition of the vitamin D3-mediated calcium absorptive mechanism in organ cultured duodenum. Biochem. Pharmacol.25, 863–864 (1976)

    PubMed  Google Scholar 

  8. Gascon-Barré, M.: Effects d'un traitement aux médicaments anticonvulsivants sur la réponse à la vitamine D3 chez le rat. Thèse de doctorat (Ph.D.), Faculté de Médecine, Université de Montréal 1975

  9. Gascon-Barré, M., Glorieux, H.F.: The effect of phenobarbital (PB) treatment on the biliary excretion of cholecalciferol (D3) and 25-hydroxycholecalciferol {25(OH)D3} in the D-repleted rat. In: Vitamin D: biochemical, chemical and clinical aspects related to calcium metabolism. (Norman, A.W., Schaefer, K., Coburn, J.W., De Luca, H.F., Fraser, D., Grigoleit, H.G., Herrath, D.v., eds.), pp. 781–783. New York: W. de Gruyter 1977

    Google Scholar 

  10. Gascon-Barré, M., Côté, M.G.: Effects of phenobarbital and diphenylhydantoin on acute vitamin D3 toxicity in the rat. Tox. App. Pharmacol. (in press)

  11. Genuth, S.M., Klein, L., Rabinovich, S., King, K.C.: Osteomalacia accompanying chronic anticonvulsant therapy. J. Clin. Endocr.35, 378–386 (1972)

    PubMed  Google Scholar 

  12. Glazko, A.J.: Diphenylhydantoin metabolism. A prospective review. Drug Metab. Dispos.1, 711–714 (1973)

    PubMed  Google Scholar 

  13. Hahn, T.J., Birge, S.J., Scharp, S.C., Avioli, L.V.: Vitamin D metabolism and phenobarbital therapy. Clin. Res.19, 50 (1971)

    Google Scholar 

  14. Hahn, T.J., Birge, S.J., Scharp, S.C., Avioli, L.V.: Phenobarbitl-induced alterations in vitamin D metabolism. J. Clin. Invest.51, 741–748 (1972)

    PubMed  Google Scholar 

  15. Horwitz, W., editor: Official methods of analysis of the association of official agricultural chemists. Third edition, Pub. Assoc. Off. Agricult. Chemists, Washington 1965

    Google Scholar 

  16. Hunter, J., Maxwell, J.D., Steward, D.A., Parsons, V., Williams, R.: Altered calcium metabolism in epileptic children on anticonvulsants. Brit. Med. J.4, 202–204 (1971)

    PubMed  Google Scholar 

  17. Kraft, D., Herrath, von, D., Schaefer, K.: Retarded growth of rats by anticonvulsant drugs. Epilepsia (Boston)15, 81–90 (1974)

    Google Scholar 

  18. Kruse, R.: Osteopathies bei Antiepilepticher Landzeittherapie. Mschr. Kinderheilk116, 378–380 (1968)

    PubMed  Google Scholar 

  19. Lunde, K.M., Rane, A., Yaffe, S.J., Lund, L., and Sjöquist, F.: Plasma protein binding of diphenylhydantoin in man. Clin. Pharmacol. Ther.11, 846–855 (1970)

    PubMed  Google Scholar 

  20. MacLaren, N., Lifshitz, F.: Vitamin D-dependency rickets in institutionalized, mentally retarded children on long-term anti-convulsant therapy. II. The response to 25-hydroxycholecalciferol and to vitamin D2. Pediat. Res.7, 914–922 (1973)

    PubMed  Google Scholar 

  21. Maynert, E.W.: Phenobarbital, mephobarbital and metharbital. Biotransformation. In: Antiepileptic drugs (Woodbury, D.M., Penry, J.K., Schmidt, R.P., eds.), Chap. 30, pp. 311–317. New York: Raven Press 1972

    Google Scholar 

  22. Noach, E.L., Woodbury, D.M., Goodman, L.S.: Studies on the absorption, distribution, fate and excretion of 4-C14-labelled diphenylhydantoin. J. Pharm. Exp. Ther.122, 301–314 (1958)

    Google Scholar 

  23. Olson, Jr., E.B., Knutson, J.C., Bhattacharyya, M.H., De Luca, H.F.: The effect of hepatectomy on the synthesis of 25-hydroxyvitamin D3. J. Clin. Invest.57, 1213–1220 (1976)

    PubMed  Google Scholar 

  24. Petruch, F., Schüppel, R.V.A., Steinhilber, G.: Effect of diphenylhydantoin on hepatic drug hydroxylation. Eur. J. Clin. Pharmacol.7, 281–285 (1974)

    PubMed  Google Scholar 

  25. Raventos, J.: The distribution in the body and metabolic fate of barbiturates. J. Pharm. Pharmacol.6, 217–235 (1954)

    PubMed  Google Scholar 

  26. Redinger, R., Small, D.M.: The effect of phenobarbital upon bile salt synthesis and pool size, biliary lipid secretion, and bile composition. J. Clin. Invest.52, 161–172 (1973)

    PubMed  Google Scholar 

  27. Remmer, H., Merker, H.J.: Effect of drugs on the formation of smooth endoplasmic reticulum and drug-metabolizing enzymes. Ann. N.Y. Acad. Sci.123, 79–97 (1965)

    PubMed  Google Scholar 

  28. Richens, A., Rowe, D.J.F.: Disturbance of calcium metabolism by anticonvulsant drugs. Brit. Med. J.4, 73–76 (1970)

    PubMed  Google Scholar 

  29. Schaefer, D., Kraft, D., Herrath, von, D., Ophz, A.: Intestinal absorption of vitamin D3 in epileptic patients and phenobarbital treated rats. Epilepsia13, 509–519 (1972)

    PubMed  Google Scholar 

  30. Schmid, F.: Osteopathien bei Antiepileptischer Dauerbehandlung. Fortschr. Med.85, 381–382 (1967)

    Google Scholar 

  31. Silver, J., Neal, G., Thomspon, G.R.: Effect of phenobarbitone treatment on vitamin D metabolism in mammals. Clin. Sci.46, 433–448 (1974)

    Google Scholar 

  32. Stamp, T.C.B., Round, J.M., Rowe, D.J.E., Haddad, J.G.: Plasma levels and therapeutic effect of 25-hydroxycholecalciferol in epileptic patients taking anticonvulsant drugs. Brit. Med. J.4, 9–12 (1972)

    PubMed  Google Scholar 

  33. Staple, P.H., Miller, W.A.: Effects of chronic administration of sodium diphenylhydantoin (“Dilantin”) on bone and teeth of the rat and hamster: a preliminary study. Calcif. Tissue Res.17, 235–248 (1975)

    PubMed  Google Scholar 

  34. Waddell, W.J., Butler, T.C.: The distribution and excretion of phenobarbital. J. Clin. Invest.36, 1217–1226 (1957)

    PubMed  Google Scholar 

  35. Winer, J.B.: Statistical principles in experimental design. New York: McGraw-Hill 1962

    Google Scholar 

  36. Yaffe, S.J., Levy, G., Matsuzawa, T., Baliah, T.: Enhancement of glucuronide-conjugating capacity in a hyperbilirubinemic infant due to apparent enzyme induction by phenobarbital. New Engl. J. Med.275, 1461–1466 (1966)

    PubMed  Google Scholar 

Download references

Author information

Author notes

  1. M. Gascon-Barré (Recipient of a Studentship from the “Département de L'Education” of the Province of Québec)

    Present address: Service d'hépatologie, Centre de Recherches Cliniques, Hôpital St-Luc, 1058, rue St-Denis, H2X 3J4, Montréal, Québec

Authors and Affiliations

  1. Department de Pharmacologie, Faculté de Médecine, Université de Montréal, Case postale 6128, H3C 3J7, Montréal, Québec, Canada

    M. Gascon-Barré (Recipient of a Studentship from the “Département de L'Education” of the Province of Québec) & M. G. Côte (Member of MRC Group in Drug Toxicology)

Authors
  1. M. Gascon-Barré
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. G. Côte
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gascon-Barré, M., Côte, M.G. Influence of phenobarbital and diphenylhydantoin on the healing of rickets in the rat. Calc. Tis Res. 25, 93–97 (1978). https://doi.org/10.1007/BF02010756

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02010756

Key words

Search

Navigation