Phenytoin pharmacokinetic parameters

Clearance (CL) 10 L/h
Volume of Distribution (Vd) 70 L
Half-life (t1/2) 4 h


Phenytoin is used in the management of generalized tonico-clonic and complex partial seizures. It may also be used in the prevention of seizures following head trauma, and in ventricular arrhythmias.

The rate of absorption varies considerably among dosage forms. Phenytoin is poorly soluble in water and is therefore commonly given as phenytoin sodium salt, which dissolves more readily. Due to its large surface area, the small intestine is the main site of phenytoin absorption. Phenytoin may be given intravenously to patients who cannot receive the drug orally or who require rapid onset of drug effect.

Phenytoin distributes into the body tissues, including the brain, within 30 to 60 minutes after reaching the systemic circulation. The drug is highly bound to both plasma proteins (mostly albumin) and to tissue components. A decrease in plasma protein binding, hence an increase in the volume of distribution, occurs in conditions reducing the amount of serum albumin (such as hepatic failure and the nephrotic syndrome), in the presence of other drugs or during the accumulation of endogenous substances competing for the albumin binding sites (as in renal failure). Phenytoin crosses the placenta and enters breast milk.

Elimination occurs primarily by biotransformation to several inactive hydroxylated metabolites. Some of these metabolites are further metabolized by conjugation with glucuronic acid. Metabolites are then mostly excreted in the urine. Phenytoin follows nonlinear (or zero-order) kinetics at therapeutic concentrations, because the rate of metabolism is close to the maximum capacity of the enzymes involved. In nonlinear kinetics, clearance and half-life fluctuate with plasma concentration. As the rate of administration increases, the plasma concentration at steady state increases disproportionately. If the rate of absorption equals or exceeds the maximum rate of metabolism, steady state is never achieved. This capacity-limited metabolism explains the interindividual variability and the lack of predictability of the phenytoin plasma concentration-time profile, because the maximum capacity varies from patient to patient. There are many conditions in which the metabolism of phenytoin is altered such as in hepatic cirrhosis or during the administration of concomitant drugs.

Chart Pharmacokinetics

Clinical implications

Because of the capacity-limited metabolism of phenytoin, a small change in the dosage form or bioavailability can produce a dramatic change in the steady state concentration. Individualization is problematic because of interindividual variability in maximum capacity. Therefore, after selection and initiation of a maintenance dose, the patient's response must be carefully evaluated not only by recording seizure frequency and watching for adverse reactions, but mainly by obtaining phenytoin plasma concentrations (Therapeutic Drug Monitoring). One or two weeks may be required for steady state to be achieved. For monitoring a plasma phenytoin concentration, it is critical to know if the observed level represents a steady state value.

The changes produced in the volume of distribution by altered binding to the plasma proteins have probably little therapeutic consequences. However, this altered binding to the plasma proteins is meaningful with respect to the interpretation of phenytoin total serum concentration: in presence of hypoalbuminemia, concomitant drug administration or renal impairment lower therapeutic concentrations must be targeted.