Summary
Plasma protein binding of phenytoin (diphenylhydantoin) in 63 epileptic patients was investigated with an ultrafiltration technique at room temperature using 14 C-labelled phenytoin. A strong correlation was found between the total and the unbound drug concentration (r = 0.97, p < 0.001). The unbound phenytoin fraction was 7.1 ± 1.0% with a range of 4.9 to 10.2%. This variation is considerably less than that reported recently by different authors. Individual phenytoin binding was reproducible when the determination was repeated several weeks later. Salivary phenytoin concentrations in 33 epileptic patients were significantly correlated to the unbound (r = 0.83) and total concentrations (r = 0.82) of phenytoin in plasma. This study confirms that the clinical practice of monitoring total phenytoin plasma concentrations is sufficient, since the unbound phenytoin fraction has only a 2-fold interindividual variation in epileptic patients, provided that they do not suffer from renal or hepatic disease.
Similar content being viewed by others
References
Arnold, K. and Gerber, N.: The rate of decline of diphenylhydantoin in human plasma. Clinical Pharmacology and Therapeutics 11: 121–134 (1970).
Bochner, F.; Hooper, W.D.; Sutherland, J.M.; Eadie, M.J. and Tyrer, J.H.: Diphenylhydantoin concentrations in saliva. Archives of Neurology 31: 57–59 (1974).
Booker, H.E. and Darcey, B.: Serum concentrations of free diphenylhydantoin and their relationship to clinical intoxication. Epilepsia 14: 177–184 (1973).
Buchtal, F.; Svensmark, O. and Schiller, P.J.: Clinical and electroencephalographic correlations with serum levels of diphenylhydantoin. Archives of Neurology 2: 624–630 (1960).
Chang, K. and Chiou, W.L.: Interactions between drugs and saliva-stimulating parafilm and their implications in measurements of saliva drug levels. Research Communications in Chemical Pathology and Pharmacology 13: 357–360 (1976).
Cook, C.E.; Amerson, E.; Poole, W.K.; Lesser, P. and O’Tuama, L.: Phenytoin and phenobarbital concentrations in saliva and plasma measured by radioimmunoassay. Clinical Pharmacology and Therapeutics 18: 742–747 (1975).
Dayton, P.G.; Cucinell, S.A.; Weiss, M. and Perel, J.M.: Dose dependence of drug plasma level decline in dogs. Journal of Pharmacology and Experimental Therapeutics 158: 305–316 (1967).
Dixon, W.J.: BMD Biomedical Computer Programs, p.439–450 (University of California Press, 1973).
Doumas, B.T.; Watson, W.A. and Biggs, H.G.: Albumin Standards and the measurement of serum albumin with bromcresol green. Clinica Chimica Acta 31: 87–96 (1971).
Hooper, W.D.; Bochner, F.; Eadie, M.J. and Tyrer, J.H.: Plasma protein binding of diphenylhydantoin. Effects of sex hormones, renal and hepatic disease. Clinical Pharmacology and Therapeutics 15: 276–282 (1974).
Hoppel, C.; Garle, M. and Elander, M.: Mass fragmentographic determination of diphenylhydantoin and its metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin in human plasma. Journal of Chromatography 116: 53–61 (1976).
Kristensen, M.; Hansen, J.M. and Skovsted, L.: The influence of phenobarbital on the half-life of diphenylhydantoin in man. Acta Medica Scandinavica 185: 347–350 (1969).
Kutt, H.; Winters, W.; Kokenge, R. and McDowell, F.: Diphenylhydantoin metabolism, blood levels and toxicity. Archives of Neurology 11: 642–648 (1964a).
Kutt, H.; Wolk, B.A.; Sherman, R. and McDowell, F.: Insufficient parahydroxylation as a cause of diphenylhydantoin toxicity. Neurology 14: 542–548 (1964b).
Lund, L.; Berlin, A. and Lunde, P.K.M.: Plasma protein binding of diphenylhydantoin in patients with epilepsy. Clinical Pharmacology and Therapeutics 13: 196–200 (1972).
Lund, L.: Effects of Phenytoin in patients with epilepsy in relation to its concentration in plasma; in Davies and Prichard (Eds) Biological effects of drugs in relation to their plasma concentrations, p.227–238 (Churchill Livingstone, Edinburgh 1973).
Lund, L.: Anticonvulsant effect of diphenylhydantoin relative to plasma levels. A prospective three year study in ambulant patients with generalized epileptic seizures. Archives of Neurology 31: 289–294 (1974).
Lunde, P.K.M.; Rane, A.; Yaffe, S.J. and Sjöqvist, F.: Plasma protein binding of diphenylhydantoin in man. Clinical Pharmacology and Therapeutics 6: 846–855 (1970).
Olsen, G.D.; Bennet, W.M. and Porter, G.A.: Morphine and Phenytoin binding to plasma proteins in renal and hepatic failure. Clinical Pharmacology and Therapeutics 17: 677–684 (1975).
Orme, M. L’E.; Borgå, O.; Cook, C.E. and Sjöqvist, F.: Measurement of diphenylhydantoin in 0.1-ml plasma samples: Gas chromatography and radioimmunoassay compared. Clinical Chemistry 22: 246–249 (1976).
Porter, R.J. and Layzer, R.B.: Plasma albumin concentration and diphenylhydantoin binding in man. Archives of Neurology 32: 298–303 (1975).
Reidenberg, M.M.; Odar-Cederlöf, I.; von Bahr, C.; Borgå, O. and Sjö qvist, F.: Protein binding of diphenylhydantoin and desmethylimipramine in plasma from patients with poor renal function. New England Journal of Medicine 285: 264–267 (1971).
Snedecor, G.W. and Cochran, W.G.: Statistical Methods. 6th ed (Ames: Iowa State University Press, 1967).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Barth, N., Alván, G., Borgå, O. et al. Two-Fold Interindividual Variation in Plasma Protein Binding of Phenytoin in Patients with Epilepsy. Clin Pharmacokinet 1, 444–452 (1976). https://doi.org/10.2165/00003088-197601060-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-197601060-00004