Very little of an orally administered dose of phenytoin is absorbed from the stomach because phenytoin is poorly soluble at a low pH. Absorption increases when the drug passes into the duodenum and continues at a slower rate in the jejunum and ileum. Absorption from the colon is poor. The oral absorption of phenytoin is somewhat irregular, prolonged, and is not first-order. The extent of its absorption is dependent of the rate at which it can enter the bloodstream. There is a maximal amount of GI fluid in which the drug can be dissolved. At higher doses, some of the drug is left undissolved, resulting in prolonged or decreased absorption. The lack of linearity has been shown in animals, where the percent absorbed is inversely related to the concentration or dose.
Phenytoin is highly (>90%) protein-bound and is extensively metabolized by the liver. Less than 5% of the drug is excreted unchanged in the liver. Phenytoin exhibits nonlinear (e.g., Michaelis-Menton) pharmacokinetics, indicating that the metabolism saturates at doses given clinically. Isoforms of the CYP2C subfamily are responsible for the metabolism of phenytoin.
Fosphenytoin is a diphosphate ester of phenytoin that is very water-soluble, making it a convenient intravenous dosage form. Its molecular weight is 1.5 times that of phenytoin. The commercial product is labeled in terms of phenytoin equivalents and should be dosed on that basis. It is rapidly converted systemically to phenytoin.8-10
Changes in hepatic blood flow do not alter phenytoin clearance because it is a low-extraction drug.10 However, loss of functional hepatocytes decreases phenytoin metabolism. Phenytoin accumulates as hepatic dysfunction increases.11 Because of decreased albumin production, liver disease is associated with decreased protein binding capacity for phenytoin. Further, bilirubin may compete for binding sites of the albumin molecule, further increasing the unbound concentration.12-17
The effect of liver diseases on fosphenytoin was evaluated in four patients with liver dysfunction, four patients with renal dysfunction, and four control subjects. There was no difference in the time to peak fosphenytoin concentrations, but the time to achieve peak plasma concentrations of phenytoin was faster in the patients with liver and renal impairment because of decreased protein binding of fosphenytoin and phenytoin.18
The absorption of phenytoin is pH dependent and is maximal in the duodenum.9 Diseases that alter gut pH and decrease duodenal dwell time are likely to alter the absorption of phenytoin.
Nasogastric feedings, which increase GI transit, decrease the absorption of phenytoin. The mechanism of this interaction remains unclear. It may result from binding of phenytoin to proteins in the feeding or from decreased time in the duodenum, where absorption is optimal.
Reviewed March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.
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