Profound Drop of Cyclosporin a Whole Blood Trough Levels Caused by St. John???s Wort (Hypericum Perforatum)

Cyclosporin A (CsA) is an immunosuppressive drug widely used in the prevention of organ allograft rejection. It has a narrow therapeutic range and, therefore, careful monitoring of CsA whole blood trough levels is essential. Low blood levels can result in rejection episodes with potential graft loss, and high CsA levels are associated with nephrotoxicity sometimes leading to chronic graft dysfunction (1). Therefore, drugs interfering with CsA blood levels are of special interest for both patients and physicians. St. John’s wort (Hypericum perforatum) is an herbal drug extract with an unknown mechanism of action. It is used for different indications, including mild and moderate depression, dysthymia, anxiety, restlessness, and psychosomatic disorders. Its antidepressive activity has been proven in different clinical trials (23). Because St. John’s wort is sold without prescription, and because of several reports in the tabloids, it is used increasingly, often without the knowledge of the treating physician. No side effects, with the exception of the rare occurrence of photosensibilization, nor interactions with other drugs are reported in the literature or by the manufacturers. We report the interaction of St. John’s wort with CsA in recipients of kidney transplants. To date, 30 patients with kidney grafts and whose CsA levels dropped significantly after the use of St. John’s wort have been observed at our institution. No other drugs were changed concomitantly, making another drug interaction highly unlikely. After initiation of therapy with St. John’s wort, a drop in CsA whole blood trough levels by a mean of 47% (range 33–62%) was observed. In turn, CsA dosage had to be gradually increased by a mean of 46% (range 15% − 115%). With discontinuation of St. John’s wort, CsA blood levels increased markedly by a mean of 187% (range 84–292%), allowing the gradual decrease of CsA to doses given before St. John’s wort treatment was initiated. An exemplary patient is shown in the Figure 1Figure 1: CsA whole blood trough levels and daily CsA dosage. Example of a representative patient. Y1-axis: CsA whole blood trough level (ng/ml). Y2-axis: Daily dosage of CsA (mg/day). X-axis: Days after the transplant.. Although the mechanism of this drug interaction is currently unknown, three possible mechanisms are conceivable. First, the absorption of CsA could be decreased by St. John’s Wort. We further investigated the absorption of CsA when taken concomitantly with St. John’s wort. Since we found normal CsA whole blood trough levels 2, 4, and 6 hr after CsA uptake, this mechanism is unlikely (data not shown). Second, St. John’s wort can induce cytochrome P-450 in the liver and/or small intestine, as shown for many drugs interacting with CsA (4). A third possible explanation would be the induction of the drug transporter P-glycoprotein in the small intestine, resulting in an increased export of CsA from the blood to the lumen of the intestine (5). Currently, it is impossible to define which of the latter two mechanisms is responsible for our finding. We are now in the process of uncover the possible mechanism. In conclusion, we have shown that St. John’s Wort significantly affects CsA blood levels. Because uncontrolled reductions of CsA blood levels caused by St. John’s Wort bear an unpredictable risk particularly for life sustaining organs such as the heart, liver or lung, caution should be taken with the administration of St. John’s Wort in patients with transplants. Th. Breidenbach1 V. Kliem M. Burg J. Radermacher M. W. Hoffmann J. Klempnauer