SERIOUS INTERACTION BETWEEN MIBEFRADIL AND TACROLIMUS1

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Abstract
Tacrolimus is metabolized by cytochrome P450 3A4 and 2D6 and has a narrow therapeutic range. We report a serious kinetic interaction between tacrolimus and mibefradil, a potent cytochrome P450 inhibitor. A 62-year-old women who had undergone liver transplantation was treated with tacrolimus for immunosuppression. For control of blood pressure, the patient was treated with nifedipine. She developed ankle edema, and nifedipine was replaced by mibefradil. Four days later, she presented with mental confusion, renal failure, and hyperglycemia, compatible with tacrolimus toxicity. In agreement with this assumption, the tacrolimus blood concentration was 100 ng/ml. Mibefradil and tacrolimus were both stopped, and the patient recovered within 1 week. Eight days after stopping mibefradil, tacrolimus was restarted at the same dosage and the subsequent plasma concentrations remained in the therapeutic range. Mibefradil increases the tacrolimus blood concentration by inhibiting its metabolism and should, therefore, not be used in patients treated with tacrolimus.