St John’s wort decreases plasma levels of quazepam, althoughthis did not reduce its effects in one study. Alprazolam appearsnot to interact,although this needs confirmation. The bioavailability of midazolam was reduced by long-term but not single dosesof St John’s wort.
Clinical evidence,mechanism, importance and management
Alprazolam 1 or 2mg was given to 7 healthy subjects on third day of a 3-day treatment period with St John’s wort (Solaray; hypericin content standardised at 0.3%) 300mg three times daily. The pharmacokinetics of alprazolam were unchanged by St John’s wort, but authors note that 3 days may have been an insufficient time for St John’s wort to fully induce cytochrome P450 isoenzymes (See reference number 1). In another study,16 healthy subjects were given St John’s wort extract 120mg (Esbericum capsules; corresponding to 0.5mg total hypericins and 1.76mg hyperforin) twice daily for 10 days. A single 1mg dose of alprazolam was given on day before treatment with St John’s wort and on last day of treatment. St John’s wort extract at this low dosage and low hyperforin content had no clinically relevant effects on pharmacokinetics of alprazolam, when compared with 12 subjects given placebo.(See reference number 2)
An open-label study in 12 healthy subjects found that a single 900mg dose of St John’s wort had no significant effect on pharmacokinetics of single doses of either oral midazolam 5mg or intravenous midazolam
0.05 mg/kg,although there was a trend for increased oral clearance. However, St John’s wort 300mg three times daily for 14 or 15 days decreased AUC and maximum plasma concentration of oral midazolam by about 50 % and 40%, respectively. Intravenous midazolam was not significantly affected. St John’s wort appears to increase metabolism of oral midazolam by induction of cytochrome P450 isoenzyme CYP3A4 in gut, resulting in reduced midazolam bioavailability (See reference number 3). Similar results were found in another study (See reference number 4).
In a placebo-controlled study,13 healthy subjects were given St John’s wort (TruNature; hypericin content standardised at 0.3%) 300mg three times daily for 14 days with a single 15mg dose of quazepam on day 14. Although St John’s wort did not affect pharmacodynamic effects of quazepam it did decrease quazepam AUC by 26 % and maximum plasma levels by 29%.This was attributed to effects of St John’s wort on cytochrome P450 isoenzyme CYP3A4, by which quazepam is metabolised (See reference number 5).
Markowitz JS,DeVane CL, Boulton DW, Carson SW, Nahas Z, Risch SC. Effect of St John’s wort (Hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers. Life Sci (2000) 66, 133–9.
Arold G,Donath F, Maurer A, Diefenbach K, Bauer S, Henneike-von Zepelin H-H, Friede M,Roots I. No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low hyperforin St John’s wort extract. Planta Med (2005) 71, 331–7.
Wang Z,Gorski C, Hamman MA, Huang S-M, Lesko LJ, Hall SD. The effects of St John’swort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther (2001) 70, 317–26.
Dresser GK,Schwarz UI, Wilkinson GR, Kim RB. Coordinate induction of both cytochromeP4503A and MDR1 by St John’s wort in healthy subjects. Clin Pharmacol Ther (2003) 73, 41–
50.
5. Kawaguchi A,Ohmori M, Tsuruoka S, Harada K, Miyamori I, Yano R, Nakamura T, MasadaM, Fujimura A. Drug interaction between St John’s wort and quazepam. Br J Clin Pharmacol (2004) 58, 403–10.