Immunosuppressants and St Johns Wort

Barone et al. reported two cases where renal transplant recipients started self-medication with St. John's wort. Both patients experienced sub-therapeutic concentrations of cyclosporine, and one patient developed acute graft rejection due to low cyclosporine concentration. Upon termination of use of St. John's wort, both patients' cyclosporine concentrations returned to therapeutic levels (28). Interaction between St. John's wort and cyclosporine is well documented in the literature (29). Bauer et al. concluded that St John's wort caused rapid and significant reduction in plasma cyclosporine concentrations. Additionally, substantial alteration in cyclosporine metabolite kinetics was also observed (30). Alschner and Klotz reported a case study where a 57-year-old kidney transplant recipient with a long-term regular intake of cyclosporine (125-150 mg/day) and prednisolone (5mg/day) and routinely monitored cyclosporine trough level (100-130 ng/mL) over the past 2 years showed a sudden drop in cyclosporine blood level to 70 ng/mL despite the daily cyclosporine dose increased to 250 mg per day. The patient admitted of taking a herbal tea mixture for depression, which contained St. John's wort. Five days after discontinuing the herbal tea his cyclosporine level was increased from 70 to 170 ng/mL (250 mg of cyclosporine per day). The dose was reduced to 175 mg per day and his trough cyclosporine level again returned to around 130 ng/mL (31). Mai et al. reported that hyperforin content of St. John's wort determines the magnitude of interaction between St. John's wort and cyclosporine. Patients who received low hyperforin-containing St. John's wort showed minimal changes in pharmacokinetic parameters and needed no dose adjustment. In contrast, the patients who received high amounts of hyperforin-containing St. John's wort needed dose increases within 3 days in order to maintain trough therapeutic concentration of cyclosporine (32).

Significant reduction in area under the curve (AUC) for tacrolimus was also observed in 10 stable renal transplant patients receiving St. John's wort. The maximum concentration of tacrolimus was also reduced from a mean value of 29.0-22.4 ng/mL following co-administration of St. John's wort (33). Bolley et al. reported a case where a 65-year-old patient who received a renal transplant in November 1998 had a trough whole blood level tracrolimus concentration between 6 and 10 ng/mL. The patient started self-medication with St. John's wort in July 2000 (600mg per day) because of depression and in August 2000 showed an unexpected low tracolimus concentration of 1.6 ng/mL. Interestingly, the serum creatinine was also decreased to 0.8mg/dL from an initial value of between 1.6 and 1.7mg/dL. When the patient stopped taking St. John's wort, tracrolimus level returned to the previous range of 6-10 ng/mL. After 1 month, the creatinine value was also gradually increased to 1.3 ng/mL. Because the patient showed no rejection episode, the new tacrolimus target level was set to 4-6 ng/mL (34). Mai et al. studied interaction of St. John's wort with tracrolimus and mycophenolic acid using 10 stable renal transplant patients. Co-administration of St. John's wort significantly reduced the AUC as well as both peak and trough blood concentrations of tracrolimus. In order to achieve sufficient immunosuppression, tacrolimus doses were increased in all patients (median 4.5-8.0 mg/day). The tacrolimus trough levels after corrected for dose decreased from a median value of 10.8ng/mL (pre St John's wort) to 3.8ng/mL 2 weeks after initiation of use of St. John's wort. Two weeks after discontinuation of St. John's wort treatment, trough concentrations were increased again to 7.6 ng/mL, and patients were adjusted again to their previous doses approximately 4 weeks after the end of the study. Interestingly, pharmacokinetic parameters of mycophenolic acid, another immunosuppressant, were not affected by co-administration of St. John's wort (35).

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