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ACETAMINOPHEN AND HYDANTOINS

Acetaminophen (e.g., Tylenol)

Hydantoins: Ethotoin (Peganone); Fosphenytoin (Cerebyx); Mephenytoin (Mesantoin); Phenytoin (e.g., Dilantin).

Significance

Onset: Delayed

Severity: Moderate

Documentation: Suspected

Effects: The potential hepatotoxicity of acetaminophen may be increased when chronic doses of hydantoins are co-administered. The therapeutic effects of acetaminophen may be reduced with simultaneous hydantoin therapy.

Mechanism: Hydantoins may induce hepatic microsomal enzymes that increase the metabolism of acetaminophen to hepatotoxic metabolites.

Management: The risk of hepatotoxicity is greatest when chronic dosing or over-dosage with acetaminophen accompanies regular hydantoin use. No special dosage adjustment or monitoring is generally required at usual therapeutic doses of acetaminophen and hydantoins.

Discussion

Hydantoins alter acetaminophen metabolism. Hydantoins apparently induce hepatic microsomal enzymes, thus accelerating acetaminophen metabolism. One study revealed that in 6 patients on chronic anticonvulsant therapy, acetaminophen clearance was 46% faster and half-life was 28% shorter in the group receiving anticonvulsants when compared with 12 controls;6 other studies have confirmed this observation.

Toxicity of acetaminophen depends largely upon the rate of formation of hepatotoxic metabolites and the rate of depletion of hepatic glutathione. Hepatic microsomal enzyme inducers (e.g., hydantoins) may place patients who overdose on acetaminophen or chronically consume therapeutic doses of acetaminophen at increased risk of hepatotoxicity.

Additional controlled studies are needed to assess the clinical importance of this potential interaction.

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