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The hepatic cytochrome P450 enzyme system is involved in the metabolism of numerous drugs.Specific enzymes are associated with the metabolism of specific drugs. The potential for drug interactions arises when one drug inhibits or induces the enzyme(s) responsible for metabolism of another drug given concurrently. Most psychotropics are metabolized by these enzymes. Clinically significant drug interactions are reported between the selective serotonin reuptake inhibitors and other psychotropics. Specifically, interactions between fluoxetine and phenytoin are reported with substantial elevations of phenytoin concentrations. Phenytoin is metabolized by the CYP2C subfamily, and fluoxetine is known to inhibit this subfamily. Similarly, sertraline also inhibits the CYP2C subfamily, but no case reports to date have been identified. To minimize and prevent these interactions, one must be aware of the P450 enzymes involved in drug metabolism. The significance of these interactions seems to rely both on the concentration of the drug at the enzyme and its potency for inhibiting the enzyme. Frequent monitoring of serum concentrations of drugs with a narrow therapeutic range would be appropriate when a potential inhibitor is added. This article describes an apparently similar interaction between sertraline and phenytoin in two elderly patients, which resulted in elevated phenytoin concentrations without symptoms of toxicity. (J Clin Psychopharmacol 1997;17:107-109).