In-Vitro Assessment of a Hypersensitivity Syndrome Associated with Sorbinil

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Abstract
Sorbinil is a hydantoin aldose reductase inhibitor that has shown promise as therapy for patients with diabetic complications such as neuropathy and retinopathy. However, as many as 10% of patients receiving sorbinil have had adverse reactions characterized by fever, skin rash, and myalgia. Our previous studies of phenytoin suggested that susceptibility to reactions might result from an inherited detoxification defect. We did the current study to determine if sorbinil is metabolized to reactive intermediates and if cells from patients with a history of a reaction to sorbinil are appropriate for the in-vitro investigation of susceptibility. Microsome-generated metabolites of sorbinil (50 microM) were toxic to normal peripheral blood lymphocytes (7.9% +/- 0.3% dead cells [mean +/- SE]). Toxicity was increased in the presence of an epoxide hydrolase inhibitor (17.5% +/- 0.3% dead cells) and abolished by an inhibitor of cytochrome P-450. In contrast to cells from healthy controls and diabetics who tolerated sorbinil (7.9% +/- 0.7% and 7.8% +/- 0.4% dead cells, respectively), cells from the six patients who had sorbinil reactions showed significantly increased toxicity from metabolites of sorbinil and phenytoin (19.7% +/- 2.3% dead cells, P less than 0.001). Cells from three patients who had reactions to phenytoin were similarly sensitive to sorbinil metabolites (23.4% +/- 0.3% dead cells). We conclude that sorbinil is oxidatively metabolized to a potentially toxic intermediate. Certain patients may be at increased risk for developing hypersensitivity reactions. Development of this important new drug has been hampered by uncommon but potentially severe reactions. An increased understanding of the steps involved in the development of adverse reactions could lead to screening tests or to the development of safer compounds.