The pharmacokinetics of tacrolimus are influenced by many factors, including genetic variability, acute infections, liver dysfunction, and interacting medications, which can result in elevated concentrations. The most appropriate management of acute tacrolimus toxicity has not been defined though case reports exist describing the therapeutic use of enzyme inducers to increase tacrolimus metabolism and decrease concentrations. We are reporting on the utilization of phenytoin to assist in decreasing tacrolimus concentrations in a case series of four solid organ transplant recipients with acute, symptomatic tacrolimus toxicity presenting with elevated serum creatinine, potassium, and tacrolimus trough concentrations greater than 30？ng/mL. All four patients had the potential causative agents stopped or temporarily held and were given 300 to 400？mg/day of phenytoin for two to three days. Within three days of beginning phenytoin, all four patients had a decrease in tacrolimus concentration to less than 15？ng/mL, a return to or near baseline creatinine concentration, and lack of phenytoin-related side effects. Therefore, phenytoin appears to be a safe and potentially beneficial treatment option in patients with symptomatic tacrolimus toxicity. 1. Introduction In solid organ transplantation, tacrolimus (FK506) has emerged as the backbone of most immunosuppressive regimens [1]. Tacrolimus exerts its immunosuppressant effects by binding to the immunophilin FK506 binding protein (FKBP12), forming a complex which inhibits calcineurin-induced dephosphorylation of the transcription factor, nuclear factor of activated T cells (NFAT) [2]. This results in suppression of interleukin-2 (IL-2) transcription and inhibition of T-cell-mediated actions. Monitoring of tacrolimus concentrations is required due to its narrow therapeutic index, in order to maintain a balance between under-immunosuppression and subsequent rejection risk with over-immunosuppression and risk of toxicities. Considerable variation exists in the pharmacokinetic profile of tacrolimus, resulting at times in challenges in maintaining therapeutic concentrations. Several factors affect the pharmacokinetics of tacrolimus, including the age or gender of the patient, liver impairment, and genetic variances in cytochrome P450 (CYP) enzymes and/or P-glycoprotein expression [3, 4]. Tacrolimus is extensively metabolized by the CYP3A4 isoenzyme, the most abundant of the CYP enzymes, constituting approximately one-third of the CYP enzymes found in intestinal lining and the liver [4]. It is also a substrate of
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