Ingrid Mai

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. Clinical Pharmacology & Therapeutics (2004) 76, 330–340; doi:10.1016/j.clpt.2004.07.004

Aim This retrospective study investigated the influence of MDR1 haplotypes derived from the polymorphisms 2677G > T (exon 21) and 3435C > T (exon 26) on the pharmacokinetics of the immunosuppressant drug tacrolimus in 73 renal transplant patients. Methods Based on both variants of SNPs 2677 and 3435, four different haplotypes and eight different genotypes were identified in the study sample. Tacrolimus trough concentrations (C₀) were compared between different SNP variants and genotypes, as well as between carriers and noncarriers of each haplotype. Additionally, CYP3A5 genotype (6956G > A) was determined. Results No significant differences were observed between groups. Differences in mean tacrolimus C₀ values between carriers and noncarriers of each haplotype ranged from −0.04 µg/litre (95% confidence interval: −0.53 to 0.60) to −23 µg/litre (−1.07 to 1.53). No association was found between CYP3A5*1/*3 genotype and tacrolimus Co concentractions. Conclusion MDR1 haplotypes derived from the SNPs 2677G > T (exon 21) and 3435C > T (exon 26) do not influence the pharmacokinetics of tacrolimus in renal transplant patients.

Background. This study investigated the effect of St John's wort (SJW) extract on the pharmacokinetics of the immunosuppressants tacrolimus (TAC) and mycophenolic acid (MPA). Methods. Ten stable renal transplant patients received 600 mg SJW extract for 14 days in addition to their regular regimen of TAC and mycophenolate mofetil. Results. Dose‐corrected AUC_(0–12) of TAC decreased significantly from 180 ng/ml/h at baseline to 75.9 ng/ml/h after 2 weeks of SJW treatment. To maintain therapeutic TAC concentrations, dose adjustments from a median 4.5 mg/day at baseline to 8.0 mg/day under SJW treatment were required. Two weeks after discontinuation of SJW, TAC doses were reduced to a median of 6.5 mg/day. MPA pharmacokinetics remained unaffected by comedication with hypericum extract. Conclusions. Administration of SJW extract to patients receiving TAC treatment can result in a serious drug interaction leading to markedly reduced TAC blood concentrations associated with the risk of organ rejection.

Cyclosporine (CyA) has made a great impact on 1-year allograft survival, however, after years, renal function deteriorates, possibly due to chronic toxicity. Recently, Mycophenolate mofetil (MMF) was introduced as a non-nephrotoxic immunosuppressant that might be effective in chronical transplant arteriolopathy. We therefore started MMF at a dose of 600 mg/m2 b. i. d. in 18 pediatric renal transplant recipients (10.8 +/- 3.9 (SD) years of age at transplantation, 11/18 with a history of rejections) with biopsy-proven chronic arteriolopathy and other signs of CyA toxicity at a mean follow up time of 6.2 +/- 2.7 (range 2.3-11.8) years after transplantation. One month prior to conversion, mean serum creatinine was 171 +/- 96 micromol/l, lower than at the time of conversion (188 +/- 100 micromol/l, P = 0.003, paired t-test). At last follow-up (median 13.7 months, range 5.0 to 25.0 months) after conversion, mean serum creatinine decreased significantly to 127 +/- 69 micromol/l (P = 0,0003, paired t-test). The CyA dosage was reduced from a mean of 150 +/- 39 mg/ m2 per day to 59 +/- 13 mg/m2 per day in 7 patients, and CyA was discontinued in 11 patients after a median period of nine months (range 1-18 months). After a median period of 21 days, a pharmacokinetic profile was performed in all patients. The mean MMF dose was 1117 +/- 319 mg/m2 per day (range 675-1774 mg/m2 per day). The mean Mycophenolic acid (MPA) trough concentration was 4.0 +/- 2.0 microg/ml, range 1.4-7.9 microg/ml. Mean 12 h MPA AUC was 70.6 +/- 28.1 (range 31.9-127) microg x h/ml. Except for one patient with diarrhea associated with a high AUC, and for one patient with a steroid-sensitive rejection episode after 566 days, no other patient experienced side effects or a rejection episode. Prednisolone was left unaltered at 2-4 mg/m2 per day. We conclude that MMF allows safe reduction of CyA with markedly better graft function, suggesting that chronical CyA-toxicity partially accounts for deteriorating allograft function.