Serum Concentrations of Free Diphenylhydantoin and their Relationship To Clinical Intoxication

Abstract

SUMMARY A rapid and inexpensive method to determine the degree of protein binding of diphenylhydantoin (and other anticonvulsants) is described; it is applicable to screening large samples of patients. The method was used in 25 selected subjects to test the hypothesis that degree of intoxication with diphenylhydantoin is related more to the serum concentration of free than of total diphenylhydantoin. The results support the hypothesis. It is suggested that the method could be used more widely and that it would reduce the variance between total serum concentration and clinical response for those anticonvulsants that are highly bound to serum proteins. RÉSUMÉ On décrit une méthode rapide et peu chère pour déterminer le degré de diphénylhydantoine liée aux protéïnes (et ďautres anticonvulsivants). Elle est applicable àľétude de larges échantillons de patients. La méthode a été utilisée sur 25 sujets sélectionnés pour tester ľhypothèse que le degréďintoxication aux hydantoïnes est plus en relation avec la concentration sérique de diphénylhydantoïne librequede la diphénylhydantoïne totale. Les résultats corroborent cette hypothèse. II est suggéré que la méthode devrait être utilisée plus largement et pourrait réduire les variations entre la concentration sérique totale et la réponse clinique pour les anticonvulsivants qui sont très largement liés aux protéïnes sériques. ZUSAMMENFASSUNG Beschreibung einer schnellen und billigen Methode zur Bestimmung des Grades der Eiweissbindung des Diphenylhydantoins (und andere Antikonvulsiva); sie ist als Screeningmethode für grosse Patientenkollektive geeignet. Die Methode wurde an 25 ausgewählten Patienten angewandt, um die Hypothese zu testen, dass das Ausmass der Intoxikation mit Diphenylhydantoin stärker von der Serumkonzentration des freien als der des Gesamtdiphenylhydantoins abhängt. Die Ergebnisse stützen die Hypothese. Es ist zu vermuten, dass die Methode weitere Anwendung finden wird und dass durch sie die lockere Beziehung zwischen der Gesamtserumkonzentration und dem klinischen Ansprechen auf solche Antikonvulsiva enger wird, die in hohem Masse an die Serumproteine gebunden sind. RESUMEN Se describe un método rápido y poco costoso para determinar la cantidad de difenilhidantoina (y otros anticonvulsivantes) que se une a las proteinas; séricas el método es aplicable al estudio de un amplio número de pacientes. Ha sido empleado en 25 enfermos seleccionados con objeto de comprobar la hipotesis de que el grado de intoxicatión por difenilhidantoina, está en relatión con la concentración en suero de difenilhidantoina libre, más que con la cifra total de dicha droga en sangre. Los resultados obtenidos estan en favor de dicha hipotesis. Se propone utilizar este método de forma más amplia con objeto de encontrar explicateón a las paradojas que se observan entre concentraciRoAn total en suero y respuesta clinica, en algunos anticonvulsivantes que se caracterizan por combinarse facilmente con las proteinas séricas.

Should we routinely measure free plasma phenytoin concentration?

“…Early studies suggested that the inter-subject variability in degree of protein binding of phenytoin may be considerable and that the free phenytoin concentration might be better correlated with clinical toxicity (Booker & Darcey, 1973;Hooper et al, 1974;Bochner et al, 1974). The latest study of phenytoin binding (Peterson et al, 1983) has reopened the controversy as to the degree of interindividual variation in binding in otherwise healthy epileptic patients.…”

“…Phenytoin is known to be highly bound to plasma proteins (approximately 90%). If there is large interpatient variability in the extent of phenytoin binding as some previous studies have suggested (Booker & Darcey, 1973;Bochner et al, 1974;Peterson et al, 1982), the total drug concentration might be a less reliable predictor of clinical effect than the free drug concentration. We thus decided to investigate the variability in phenytoin binding in epileptic patients receiving the drug.…”

Plasma concentrations of unbound phenytoin in the management of epilepsy.

“…As unbound drug represents the active form which equilibrates with tissues and because of the potential variability in phenytoin protein binding, it is desirable that the active unbound rather than the total concentration of the drug is measured in monitoring therapy. It has already been shown that phenytoin toxicity correlates better with the unbound rather than the total concentration of the drug (Booker & Darcey, 1973). The correlation between the unbound concentration and the therapeutic effect has not been formally examined although phenytoin saliva concentration, which reflects unbound plasma concentration, has been shown to relate well with clinical effect (Knott et al, 1982;McAuliffe etal., 1977;Reynolds etal., 1982).…”

CSF Concentrations and Serum Protein Binding of Carbamazepine and Carbamazepine‐10, 11‐epoxide in Epileptic Patients

“…Modification of plasma protein binding due to diseases or displacing effects of other drugs has been shown to alter dramatically the toxic effects of several compounds (Reidenberg & Affrine, 1973;Anton, 1973). Recent data (Booker & Darcey, 1973;Glassman, Hurwic, Kanzler, Shostak & Perel, 1974) tend to suggest that, at variance with previous results (BorgA, Azarnoff, Forshell & Sjoqvist, 1969), important inter-individual differences in plasma protein binding may be observed in patients undergoing chronic treatment, in the absence of specific phenomena such as displacement, or alteration in proteinemia. Such conditions may be of importance for the therapeutic outcome and give an explanation of the considerably large therapeutic range observed for several drugs.…”