We report here acute rejection in two transplant patients due to a metabolic interaction of St John´s wort and cyclosporin

AIM: This study investigated the effects of St John's wort extract (SJW) on the pharmacokinetics and metabolism of the immunosuppressant cyclosporin A (CSA). METHODS: In an open-label study, 11 renal transplant patients received 600 mg SJW extract daily for 14 days in addition to their regular regimen of CSA. Blood concentrations of CSA and its metabolites AM1, AM1C, AM9, AM19, and AM4N were measured by HPLC. RESULTS: After 2 weeks of SJW coadministration, dose-corrected AUC0-12, Cmax and Ctrough values for CSA decreased significantly by 46%[geometric mean ratio baseline/SJW (95% CI): 1.83 (1.63-2.05)], 42%[1.72 (1.42-2.08)], and 41%[1.70 (1.17-2.47)], respectively. CSA doses were increased from a median of 2.7 mg day(-1) kg(-1) at baseline to 4.2 mg day(-1) kg(-1) at day 15, with the first dose adjustment required only 3 days after initiation of SJW treatment. Additionally, the metabolite pattern of CSA was substantially altered during SJW treatment. Whereas dose-corrected AUC values for AM1, AM1c and AM4N significantly decreased by 59%, 61%, and 23% compared with baseline, AUC values for AM9 and AM19 were unchanged. Following the increase in CSA dose, observed AUC and Cmax values for AM9, AM19, and AM4N increased by 20-51% and 43-90%, respectively. CONCLUSION: Administration of SJW extract to patients receiving CSA treatment resulted in a rapid and significant reduction of plasma CSA concentrations. Additionally, the substantial alterations in CSA metabolite kinetics observed may affect the toxicity profile of the drug

BACKGROUND: Many drugs are cosubstrates of cytochrome P450 (CYP) 3A and MDR1; furthermore, their disposition is markedly affected by pretreatment with inducing agents, including St John's wort. Such drug interactions reflect induction of both proteins through a common mechanism involving the steroid X receptor/pregnane X receptor. However, the relative contributions of enhanced metabolism and efflux transport to the overall induction process are unknown. METHODS: The effects of 12 days' pretreatment with St John's wort on the disposition of selected in vivo probe drugs were determined in 21 young healthy subjects. Midazolam after oral and intravenous administration was used to assess CYP3A activity in both the intestinal epithelium and the liver, whereas the disposition of fexofenadine after an oral dose was assumed to be a measure of MDR1 function, and the oral plasma concentration-time profile of cyclosporine (INN, ciclosporin) was considered to reflect both CYP3A and MDR1 activities. RESULTS: St John's wort markedly affected the plasma concentration-time profiles of all of the drugs, with associated increases in their clearance. With midazolam, the enhancement was considerably less after intravenous administration (approximately 1.5-fold) than after oral administration (approximately 2.7-fold), and estimated intestinal and hepatic extraction ratios were higher by approximately 1.2- to 1.4-fold. By contrast, the oral clearances of fexofenadine and cyclosporine were equally increased by approximately 1.6-fold and 1.9-fold, respectively; these changes were both statistically less than for midazolam's oral clearance and greater than its estimated intestinal extraction. CONCLUSIONS: Although the disposition of all 3 drugs was altered by St John's wort, the extent of induction measured by oral clearance was different with CYP3A activity (midazolam), apparently increasing more than MDR1 function (fexofenadine), whereas with cyclosporine the change in oral clearance appeared to be more closely associated with the increase in MDR1 rather than CYP3A, despite the fact that both proteins are importantly involved in its disposition. These discordances indicate that, although a common molecular mechanism may be involved, the quantitative aspects of induction are complex and depend on the particular drug and the relative contributions of CYP3A and MDR1 in its disposition

OBJECTIVE: To report a probable drug interaction between the herbal dietary supplement St. John´s wort and cyclosporine. CASE REPORT: A 29-year-old white woman who received a cadaveric kidney and pancreas transplant, with stable organ function and stable cyclosporine concentrations began self-medicating with St. John´s wort. After taking St. John´s wort supplements for four to eight weeks, her cyclosporine concentrations became subtherapeutic; this was associated with organ rejection. Four weeks after stopping St. John´s wort, her cyclosporine concentrations again became therapeutic. Subsequent to this rejection episode, she has developed chronic rejection and now has returned to dialysis. DISCUSSION: St. John´s wort is suspected to be a significant inducer of CYP3A4 isoenzyme activity and of P-glycoprotein (P-gp) expression, both of which are important in the metabolism and absorption of cyclosporine. Cyclosporine exhibits a relatively small therapeutic window and is sensitive to medications that can modulate the CYP3A4 isoenzyme and P-gp in both the liver and small intestines. CONCLUSIONS: Patients taking St. John´s wort concomitant with other prescription medications whose absorption and metabolism are mediated by the CYP3A4 isoenzyme and P-gp require close monitoring. Patient medication histories should include inquiries into the use of herbal dietary supplements

Blood levels of phenytoin, total thyroxine, and free thyroxine were determined in 10 epileptic women during and following pregnancy. Although total thyroxine concentrations of phenytoin-treated subjects were significantly lower than control values, pregnancy did not appear to diminish the relative increase in total thyroxine seen in normal pregnancy. Free thyroxine concentrations, which were equally depressed at all test times, remained at low euthyroid levels during pregnancy. Following delivery, 3 patients developed free thyroxine levels below 1.0 ng/100 ml. Phenytoin dosage was increased to improve seizure control but produced relatively low blood levels during pregnancy. Following delivery, phenytoin dosage was slightly decreased but produced a significant increase in phenytoin blood levels. The potential effects of phenytoin-related changes in maternal and fetal thyroxine levels are discussed

Contrary to common belief, over-the-counter herbal remedies may cause clinically relevant drug interactions. With the enclosed report we would like to alert other physicians that herbal extracts of Saint John´s wort (Hypericum perforatum) may cause a sudden remarkable decrease of cyclosporin trough concentrations. A kidney transplantation patient treated with 75 mg bid doses of cyclosporin for many years experienced a sudden drop in her cyclosporin trough concentrations. This change was in temporal relationship to hypericum extract comedication, and a re-challenge gave similar results. The mean dose-normalized cyclosporin concentration during this comedication (90% confidence interval) was 0.48 (0.43 to 0.54) ng/(ml x mg) and was constantly below the respective concentration without the herbal remedy (0.84 (0.79 to 0.89) ng/(ml x mg)). This difference in the pharmacokinetics of cyclosporin indicates a relevant influence of St John´s wort extract. The potential clinical consequence of this pharmacokinetic herb-drug interaction is apparent, since low cyclosporin levels are associated with an increased risk of rejection after organ transplantation and are usually not suspected upon intake of plant products. In view of the permanently increasing use of St John´s wort preparations for various indications and the clinical relevance of this interaction, our report may contribute to the ongoing debate on the prescription status and safety of hypericum extracts

OBJECTIVE: Hyperforin (HYF) has been discussed as a potential cause of the reduction in the bioavailability of numerous drugs seen with St John's wort (SJW) comedication. This study compared the effects of 2 SJW preparations with high and low HYF content on the pharmacokinetics of cyclosporine (INN, ciclosporin) (CSA). METHODS: In a crossover study, 10 renal transplant patients were randomized into 2 groups and received SJW extract (900 mg/d) containing low or high concentrations of HYF for 14 days in addition to their regular regimen of CSA. After a 27-day washout phase, patients were crossed over to the other SJW treatment for 14 days. Blood concentrations of CSA were measured by immunoassay. RESULTS: The study showed a significant difference between the effects of the 2 SJW preparations on CSA pharmacokinetics (area under the plasma concentration-time curve within one dosing interval [AUC 0-12 ], P < .0001, ANOVA). AUC 0-12 values (monoclonal) with high-HYF SJW comedication were 45% lower (95% confidence interval [CI], -37% to -54%; P < .05, Student-Newman-Keuls test) than for low-HYF SJW. The dose-corrected AUC 0-12 for CSA (monoclonal) decreased significantly compared with baseline by 52% (95% CI, -46% to -56%; P < .05) after 2 weeks of comedication with high-HYF SJW. Values of peak concentration in plasma and drug concentration at the end of one dosing interval were affected to a similar extent, with reductions by 43% (95% CI, -36% to -48%) and 55% (95% CI, -48% to -60%), respectively. In addition, a 65% (95% CI, 53% to 85%; P < .05) increase in daily CSA doses was required during high-HYF SJW treatment. In contrast, coadministration of low-HYF SJW did not significantly affect CSA pharmacokinetics and did not require CSA dose adjustments compared with baseline. CONCLUSION: HYF content of SJW extracts significantly affects the extent of the pharmacokinetic interaction between CSA and SJW

The use of herbal medicine has become increasingly popular in the United States. Hypericum perforatum (St. John´s wort) is an herbal extract that is used widely as a folk remedy for depression. In this case report, we describe a kidney transplant recipient who developed marked reduction of cyclosporine therapeutic activity after the self-initiation of St. John´s wort. Postulated mechanisms for the ability of this herbal extract to interact with pharmaceutical medications are presented, and the existing literature is reviewed

Immunosuppressive therapy in patients after liver transplantation requires careful monitoring of blood levels for immunosuppressive agents such as cyclosporin A. A variety of drugs are capable of interfering with the metabolism of cyclosporin A. We observed a 63-year-old patient who received a liver allograft for cryptogenic liver cirrhosis in 1998. This patient developed severe acute rejection 14 months after transplantation which was associated with a sudden drop in cyclosporin A levels. Two weeks previously, he had started taking the herbal drug Hypericum perforatum (2 x 900 mg/day) for increasing episodes of depression. The cyclosporin A dosage later had to be doubled, which caused some side effects. Finally, an assessment of oral cyclosporin A resorption suggested an enhanced cyclosporin A metabolism. Hypericum perforatum was stopped. Both cyclosporin A dosage and blood levels immediately returned to normal. The liver function recovered completely. In conclusion, this observation is a previously undescribed drug interaction of a widely used herbal drug (Hypericum perforatum, i.e. St. John´s wort) in a patient after liver transplantation

Hos 3 patienter i ciclosporin behandling ses en betydelig nedsµttelse af steady state koncentrationen ved samtidig behandling med perikum. Der er ikke tegn pÕ afst°delse

Der ses en betydelig nedsµttelse af ciclosporin koncentrationen. Der ses ingen farmakodynamiske µndringer. +rsagen er samtidig behandling med perikum. Senere unders°gelse pÕ patient viser igen en nedsat ciclosporin koncentration ved samtidig beahndling med perikum