Table 4.
Clinical trials of St. John’s wort co-administered with other drugs
| Interaction/Co. administration | Extract/Compd. | Dosing & duration | Study design & sample size | Result | Ref. |
|---|---|---|---|---|---|
| Ambrisentan | Jarsin® | 300 mg TID; 10 days (tenth to twentieth day of study) | An open-label, monocentric, one-sequence, crossover, multiple-dose clinical trial; 20 healthy volunteers (10 CYP2C19 extensive, 4 poor, and 6 ultra-rapid metabolizers) (mean age of 31.3 ± 7.7 years) | Equality of ambrisentan concentration in extensive, ultra-fast, and poor metabolizers ↓ Ambrisentan exposure (17–26%) in all genotype groups No significant reduction in the effect of CYP2C19 on the metabolism of ambrisentan |
(89) |
| Atorvastatin | Movina® | 300 mg BID; 12 weeks | An open, crossover RCT; 16 patients with hypercholesterolemia (55-72 years) | ↑ LDL cholesterol serum level significantly ↑ Total cholesterol No statistically significant change in HDL cholesterol and triglycerides |
(88) |
| Boceprevir | Ucalm®1 | 2 tablets QD; 56 days (SJW on days 1–14, SJW plus boceprevir (SJW on days 22–35 and together on days 31–35) and boceprevir on days 52–56, separated by 7-day washout periods) | Phase I, open-label, three-period, cross-over trial; 17 healthy subjects (26–49 years) | Failure to observe clinical effects on the plasma concentration of boceprevir (or its metabolite) | (121) |
| Bupropion | SJW extract | 325 mg TDS; 2 weeks | An open-label, two-phase design; 18 healthy males | ↑ Oral clearance of bupropion ↓ Area under the concentration versus time curve extrapolated to infinity of bupropion |
(93) |
| Carbamazepine | Extract standardized to 0.3% hypericin | 300 mg TID; 2 weeks | An Open-label Trial; 8 healthy subjects |
No change in Cmax and AUC of carbamazepine | (122) |
| Cyclosporin A | Jarsin® | 600 mg QD; 2 weeks | An open-label study; 11 renal transplant patients (34–59 years) | ↓ AUC0-12, C max and C trough values for cyclosporin significantly by 46% ↓ Plasma cyclosporin concentrations |
(94) |
| Cyclosporine | Jarsin® with low (0.1 mg) and high (7.0 mg) concentrations of hyperforin | (900 mg/d) containing low or high concentrations of hyperforin; 2 weeks | A crossover study; 10 renal transplant patients (25–65 years) | ↓ Plasma ciclosporine levels significantly Not influence cyclosporine pharmacokinetics significantly by extract with low hyperforin content |
(85) |
| Cytochrome P450 enzymes and P-glycoprotein | Rebalance®2 500 | 500 mg QD; 10 days | An open-label, non-randomized, single-sequence study; 20 healthy volunteers (18-55 years) | No pharmacokinetic interactions of Ze 117 for CYPs and P-glycoprotein No relevant pharmacokinetic interactions with important CYPs and P-glycoprotein |
(86) |
| Digoxin | variable formulation of SJW | Variable concentration of hyperforin; 2 weeks | A parallel-group RCT; 96 healthy volunteers (18-40 years) | No significant interaction with 2 g powder without hyperforin, tea, juice, oil extract, hyperforin-free extract (Ze 117), or low daily doses of hyperforin-containing Hypericum powder (1 g, 0.5 g) and placebo ↓ AUC0-24, Cmax, and Ctrough of digoxin with high-dose hyperforin-rich extract (LI 160) |
(87) |
| Docetaxel | Hyperiplant®3 | 300 mg TDS; 2 weeks | An open-label, non-randomized, crossover study; 10 patients with histological or cytological proof of cancer for whom treatment with docetaxel (up to 18 years) | ↓ Mean area under the docetaxel plasma concentration-time curve significantly ↑ Docetaxel clearance significantly ↓ Incidence of docetaxel-related toxicities |
(95) |
| Effect of macitentan before and during SJW on the pharmacokinetics of rivaroxaban | Jarsin® | 300 mg TID; 12 days | An open-label, monocentric, two-period, one sequence phase I clinical trial; 12 healthy volunteers (up to 18 years) | ↑ CYP3A activity by 272% ↓ GMR of rivaroxaban AUC and Cmax by 25% ↓ GMR of macitentan AUC by 48% and of Cmax by 45% |
(99) |
| Effect of SJW and ritonavir on Cyp3A enzyme activity | Jarsin® | 300 mg TDS; 2 weeks | An open, fixed-sequence study design; 12 healthy Caucasian participants (mean age of 26±3.25 years) |
↑ (AUC)0–8 h of midazolam | (111) |
| Effect of SJW on CYP2C19 activity | Extract with 4% hyperforin and 0.3% hypericin | 300 mg TDS; 2 weeks | A two-phase, randomized, crossover design; 12 healthy males (6 extensive metabolizers of CYP2C19 and 6 poor metabolizers) (18–25 years) | ↑ CYP2C19 activity significantly No significant alteration in CYP2C19 poor metabolizers |
(106) |
| Effects of SJW and ketoconazole (CYP3A inhibitor) on CYP3A | Jarsin® | 300 mg TDS; 8 days | A two-phase, randomized, cross-over, open, monocentral trial; Twelve healthy, male participants (22–49 years) | ↓ Clearance of midazolam in relation to baseline (82%) strongly by a single dose of ketoconazole when used concomitantly with SJW | (110) |
| Fluoxetine | LI-160 | 300 mg TDS; 12 weeks | An active, parallel-group, double-blind RCT; 134 patients with MDD (mean age of 37.3 ± 11.0) | ↓ HAMD-17 scores at the endpoint in the SJW group ↑ Remission rates (HAMD-17 <8) |
(109) |
| Ibuprofen | Extract standardized with 0.3% hypericin | 300 mg TID; 3 weeks | An open-label trial; 8 male subjects | No change in Cmax and AUC of ibuprofen | (123) |
| Imatinib | Kira® | 300 mg TID; 17 days | An open-label trial;12 healthy subjects (20–51 years) | ↓ Cmax, AUC, and t1/2 ↑ Clearance of imatinib |
(115) |
| Indinavir | Extract standardized with 0.3% hypericin | 300 mg TID; 2 weeks | An open-label study; 8 healthy males | ↓ Cmax and AUC | (112) |
| Intravenous fentanyl | Extract Kira® | 300 mg TID; 20 days | A randomized parallel-group design; 16 healthy subjects (21–41 years) | No effect on fentanyl pharmacokinetics, pharmacodynamics, or clinical effects No influence on analgesia, cognitive performance, or somatic cognitive–affective effects of fentanyl |
(90) |
| Irinotecan | SJW extract (300 mg)4 | 300 mg TDS; 18 days | An unblinded, randomized crossover study;5 cancer patients |
↓ Plasma levels of SN-38 (active metabolite of irinotecan) | (101) |
| Ivabradine | Jarsin® | 300 mg TID; 2 weeks | A non-randomized, open-label trial; 18 healthy subjects (18-40 years) | ↓ C max and AUC of ivabradine and its active metabolite | (124) |
| Metformin | Modigen®5 | One capsule BID; 3 weeks | An open cross-over study; 20 healthy male subjects (18–64 years) who received 1 g of metformin twice daily for 1 week | ↓ Renal clearance of metformin ↓ Area under the glucose concentration–time curve ↑ Glucose tolerance by enhancing insulin secretion independently of insulin sensitivity |
(102) |
| Midazolam | Capsule with low hyperforin (total hyperforin 0.06 ± 0.001 mg and total hypericin 0.60 ±0.03 mg) | 500 mg BID; 2 weeks | An open-label one-sequence crossover, single-dose study; 20 healthy male volunteers (mean age of 24.9 ± 2.3 years) | ↓ Midazolam AUC0–∞ slightly No significant change in Cmax, t1/2 and tmax of midazolam Mild induction of CYP3A |
(91) |
| Oral contraceptives | SJW extract containing 0.3% hypericin and 20 ng/ml average steady-state concentrations of hyperforin | 300 mg TDS; for 3 consecutive 28-day menstrual cycles | Clinical trials; 12 healthy premenopausal women (mean age of 27 ± 7 years) | ↑ Oral clearance of norethindrone ↓ Half-life of ethinyl estradiol significantly ↑ CYP3A activity |
(96) |
| Oral contraceptives | Extract with 0.3% hypericin and 3.7% hyperforin | 300 mg TDS; 4 consecutive 28-day cycles | A single-blind sequential trial; 16 healthy women | ↓ Dose exposure from the contraceptive significantly by 13–15% ↑ Breakthrough bleeding and follicle growth and ovulation |
(103) |
| Oral oxycodone | Jarsin® | 300 mg TID; 2 weeks | A cross-over RCT; 12 healthy volunteers (mean age of 23 ± 4 years) | ↓ AUC of oxycodone by 50% ↓ The plasma concentrations of oral oxycodone |
(97) |
| Oral S-ketamine | Jarsin® | 300 mg TID; 2 weeks | A cross-over RCT; 12 healthy subjects (20–35 years) | ↓ (AUC0–∞) of ketamine by 58% ↓ Cmax of ketamine by 66% No significant changes in the behavioral or analgesic effects of ketamine |
(104) |
| Paroxetine | WS® 5570 | 900 mg/day (initially non-responders’ doses were increased to 1800 mg/day); 6 weeks | A double-blind, double-dummy, reference controlled, multicenter non-inferiority RCT; 251 adult outpatients with acute major depression (18-70 years) | ↓ Hamilton depression total score ↓ Incidence of adverse events |
(108) |
| Platelet response in patients resistant to clopidogrel after PCI | SJW extract | 300 mg TDS; 2 weeks after PCI | A single-center 2:1 open-label RCT; 23 patients’ non-responders to 600 mg clopidogrel (18–75 years) | ↑ Residual platelet reactivity during the first-month post-PCI Changed PRU significantly |
(84) |
| Prednisone | Extract standardized with hypericin 0.3% | 300 mg (tablets) TID; 4 weeks | A single-dose study; 8 healthy males (19–36 years) | No significant alterations in the pharmacokinetic parameters for prednisone or prednisolone |
(92) |
| Repaglinide | SJW extract | 325 mg TID; 14 days | A two-phase, randomized, crossover study; 15 healthy subjects with specific solute carrier organic anion transporter family member 1B1 (SLCO1B1) Genotypes (19–24 years) |
No effect on the total area under the plasma concentration-time curve from time zero to infinity (AUC∞), the elimination half-life (t½), or the peak plasma concentration (Cmax) No significant effect on the blood glucose-lowering and insulin-elevating effects of repaglinide |
(125) |
| Response of clopidogrel in hypo-responsive volunteers | Kira® | 300 mg TID; 2 weeks | A prospective, randomized, double-blind, pilot study; 10 healthy clopidogrel hypo responsive volunteers (18–70 years) | ↓ Platelet aggregation ↑ CYP3A4 activity |
(107) |
| Rifampicin | Jarsin® | Flexible dose (300–600 mg TID) (first 300 mg QD for 14 days, second 300 mg TID for 14 days and finally increased to 600 mg TID within 3–6 days | Clinical phase I trial; 12 healthy volunteers (six males and six females) | ↑ Dermatological and neurological symptoms in sun-exposed areas only in women | (98) |
| Rosuvastatin | Capsule including 300 mg SJW 80 mg rosemary, and 40 mg spirulina |
300 mg BID; 20 weeks | Case report; one male with hypercholesterolemia |
↑ LDL-cholesterol ↑ Total-cholesterol |
(126) |
| Simvastatin | Movina®6 | 300 mg BID; 4 weeks | A controlled, randomized, open, crossover study; 24 patients with hypercholesterolemia (54–78 years) | ↑ LDL-cholesterol significantly ↑ Total-cholesterol |
(88) |
| Tacrolimus | Jarsin® | 300 mg TDS; 18 days | A clinical trial;10 healthy volunteers (20–30 years) | ↓ AUC of tacrolimus significantly ↑ Oral clearance and oral volume of distribution at steady state of tacrolimus |
(100) |
| Theophylline | TruNature® with 0.3% hypericin | 300 mg TDS; 15 days | A randomized, open-labeled, crossover study; 12 healthy Japanese male volunteers (mean age of 25.0 ±6.4 years) | No significant changes in the pharmacokinetics of theophylline in plasma |
(127) |
| Warfarin | Tablets contain SJW with 12.5 mg hyperforin and 0.825 mg hypericin and Korean ginseng | One tablet TID; 3 weeks | An open-label, crossover randomized trial; 12 healthy males (20–40 years) | ↓ AUC and t1/2 ↑ Clearance of S-warfarin and R-warfarin |
(120) |
| Zolpidem | LI160 | 300 mg TDS; 2 weeks | A controlled, open-label, non-randomized, fixed-dose schedule design; 14 healthy males (mean age of 21.1 ±1.5 years) | ↓ Zolpidem plasma concentration by enhancing CYP3A4 activity | (105) |
1 It includes 300 mg of SJW extract per tablet; 2 SJW dry extract Ze 117 contained hyperforin (0.96 mg) per film-coated tablet; 3 Dry extract standardized to 0.36–0.84 mg hypericin and 9–19 mg hyperforin; 4 Bio Nutrition Health Products, Den Bosch, The Netherlands; 5 Capsule with 240–294 mg dry extract of SJW (900 μg total hypericin); 6 Capsules contained 300 mg SJW extract standardized to 3-6 % hyperforin
SJW: St John’s wort