A study of the pharmacokinetics of phenytoin (diphenylhydantoin) in epileptic patients, and the development of a nomogram for making dose increments

Abstract

Phenytoin is metabolized to its parahydroxylated derivative by hepatic microsomal enzymes. This hydroxylation is a saturable process, that is, the rate of metabolism fails to increase in proportion to the serum concentration. This leads to a nonlinear relationship between the maintenance dose of the drug and the resulting steady-state serum level. As the therapeutic range of serum levels is reached, the increase in level produced by a given increment in dose becomes progressively greater. An increment of only 50-100 mg will carry the serum level from the lower to the upper limit of the therapeutic range in most patients. Thus, problems in bioavailability, noncompliance, and drug interactions are an important practical problem with this drug. Monitoring serum phenytoin levels during chronic therapy is an invaluable therapeutic aid, enabling dosage adjustments to be made in order to achieve a level within the therapeutic range. A nomogram is presented in this paper in order to assist the physician in making dosage increments.