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Diphenylhydantoin potency and plasma protein binding.

D W Shoeman, D L Azarnoff

The Journal of Pharmacology and Experimental Therapeutics

|October 1, 1975

Summary

Phenylbutazone increases diphenylhydantoin (DPH) potency by affecting total plasma levels, not unbound concentrations. This highlights that DPH’s anticonvulsant effect relies solely on its unbound drug levels in plasma.

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Area of Science:

Pharmacology
Neuroscience
Toxicology

Background:

Diphenylhydantoin (DPH) is an established anticonvulsant medication.
Understanding factors influencing DPH efficacy is crucial for optimizing seizure control.
Drug interactions can significantly alter the pharmacokinetics and pharmacodynamics of anticonvulsants.

Purpose of the Study:

To investigate the impact of phenylbutazone on the anticonvulsant potency of diphenylhydantoin (DPH) in rats.
To determine how phenylbutazone affects the total and unbound plasma concentrations of DPH.
To elucidate the relationship between DPH plasma concentrations (total vs. unbound) and its anticonvulsant activity.

Main Methods:

Rats were administered diphenylhydantoin (DPH) orally to assess its anticonvulsant potency against maximal electroshock seizures.
Phenylbutazone was administered intravenously (100 mg/kg) one hour prior to DPH administration and seizure testing.
Total and unbound plasma concentrations of DPH were measured, alongside potency assessments.

Main Results:

Phenylbutazone administration significantly increased the anticonvulsant potency of DPH when measured by dose and total plasma drug concentration.
However, phenylbutazone did not alter the anticonvulsant potency of DPH when assessed based on the unbound plasma drug concentration.
A clear correlation was observed between the unbound DPH plasma concentration and its anticonvulsant effect.

Conclusions:

The anticonvulsant action of diphenylhydantoin (DPH) is directly dependent on the concentration of unbound drug in the plasma.
Total plasma concentration and administered dose of DPH do not solely determine its anticonvulsant efficacy.
Phenylbutazone's effect on DPH potency is mediated through alterations in total plasma concentration, not by changing the pharmacologically active unbound fraction.

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