Table 3.
Population characteristics, St John’s wort (SJW) dose and CYP3A-related outcomes for studies assessing extracts with unknown (or uncertain) hyperforin content
| Trial | Subjects | Dosage regime for extract | Drug, probe or marker regime | CYP3A-related outcomes |
|---|---|---|---|---|
| Early Indena S.p.A extract standardized to 0.3% hypericin | ||||
| Burstein 2000 [41] | 8, 38% female, age range 24–43 | 300 mg t.d.s. for 14 days (H 2.7 mg day−1) | Carbamazepine for 22 days (dose built up to 400 mg over 7 days), followed by SJW comedication for 14 days; pharmacokinetic test days before and after SJW treatment | No significant change in Cmax, Tmax, AUC0−24 or oral clearance of carbamazepine or metabolite carbamazepine-10,11-epoxide |
| Piscitelli 2000 [42] | 8, 25% female, age range 29–50 | 300 mg t.d.s. for 14 days (H 2.7 mg day−1) | Indinavir 800 mg t.d.s. on pharmacokinetic tests days (additional 800 mg given on the following day) before and after SJW treatment | Indinavir AUC0−8 decreased by 57% (P = 0.0008) |
| Roby 2000 [43] | 13, 69% female, age range 20–41 | 300 mg t.d.s. for 15 days (H 2.7 mg day−1) | 24 h 6BHC/C before and after SJW treatment | 6BHC/C increased by 83% (P = 0.003, range of change −25% to 259%) |
| Unknown SJW extract E, standardized to 0.3% hypericin | ||||
| Gurley 2005 [21] | 12, 50% female, age range 60–76 | 300 mg t.d.s. for 28 days (H 0.27 mg day−1, HF4.8 mg day−1) | Midazolam p.o. 8 mg before and after 27 days’ SJW | 141% increase in the mean 1-h 1-hydroxymidazolam/midazolam serum ratio (P < 0.001) with a presupplementation mean of 0.379 (95% CI 0.250, 0.507) and a postsupplementation mean of 0.389 (95% CI 0.633, 1.195) |
| Unknown SJW extract F, standardized to 0.3% hypericin | ||||
| Kawaguchi 2004 [44] | 13, 0% females, age 34 ± 6 | 300 mg t.d.s. for 14 days (H 2.7 mg day−1) | 24 h urinary 6BHC/C and quazepam 15 mg after 14 days’ placebo and 14 days’ SJW treatment (4-week interval between) | The mean 6BHC/C ratio was 96% higher after SJW compared with after placebo (P < 0.05); quazepam mean AUC0−48 was 26% less and the Cmax was 29% less after SJW than after placebo (P < 0.05) |
| Sugimoto 2001 [45] | 8, 0% females, age range 26–44 | 300 mg t.d.s. for 14 days (H 2.7 mg day−1) | Simvastatin 10 mg after 14 days’ placebo and 14 days’ SJW treatment (4-week interval between) | AUC0−24 of pro-drug simvastatin lactone (metabolized to inactive metabolites by CYP3A) and simvastatin hydroxy acid (active metabolite) were 48% and 62% (P < 0.05) less, respectively, after SJW treatment compared with placebo |
| Morimoto 2004 [46] | 12, 0% females, age 25 ± 6 | 300 mg t.d.s. for 15 days (H 2.4 mg day−1) | Theophylline 400 mg after 14 days’ SJW or no treatment (19–35-day interval between) | No change in theophylline AUC curve was observed after 14 days’ SJW treatment (95% CI −9.3%, 23% change; P = 0.41); a trend towards a slight increase in 1-methyluric acid, a CYP1A2 and possibly a CYP3A metabolite |
| Unknown SJW extract G, standardized to 0.3% hypericin | ||||
| Markowitz 2000 [47] | 7, 43% female, age range 24–32 | 300 mg t.d.s. for 4 days (H 2.7 mg day−1) | Alprazolam (3 subjects 1 mg, 4 subjects 2 mg) before and after 3 days of SJW treatment; SJW treatment continued during pharmacokinetic testing for a further day | Alprazolam mean AUC0–∞ decrease of 41.3% (P = 0.14) |
| Unknown SJW extract H | ||||
| Mathijssen 2002 [48] | 5 cancer patients, 60% female, age range 54–66 | 300 mg t.d.s. for 18 days | I.v. irinotecan 350 mg m−2 given at 21-day intervals; subjects were randomly assigned to SJW 14 days prior (plus 4 days after) or no treatment 14 days prior | Active metabolite SN-38 AUC decreased by 42% (95% CI 14, 70; P = 0.033) |
| Unknown SJW extract I | ||||
| Xie 2005 [49] | 30, 26% female, age range 19–51 | 300 mg t.d.s. for 10 days | Oral midazolam 5 mg and i.v. midazolam 1 mg before and after SJW treatment | 56% increase in midazolam systemic clearance (P < 0.001); 45% decrease in absolute bioavailability of midazolam (P < 0.001), no difference between ethnic groups (black, White, Hispanic, Chinese, Indian, Malay) |
H, Hypericin; HF, hyperforin (italics, results from independent assay); CSA, cyclosporin A; 6BHC/C, 6-beta-hydroxycortisol/cortisol ratio; t.d.s., three times daily; b.d., twice daily.