The extent of induction of CYP3A by St. John’s wort varies among products and is linked to hyperforin dose

Abstract

The extent of induction of CYP3A varies among St. John's wort products and depends on hyperforin dose.

No clinically relevant CYP3A induction after St. John’s wort with low hyperforin content in healthy volunteers

“…In vitro testing of CYP3A induction by six commercial St. John's wort extracts with a 62-fold variation in hyperforin content resulted in a significant correlation of magnitude of induction and hyperforin content, but no correlation with hypericins and flavonoids [17]. This agrees with the results of a drug interaction study with six St. John's wort preparations in healthy volunteers, where the decrease in oral midazolam exposure, used as a CYP3A phenotyping probe, was correlated with hyperforin dose, but not with hypericin dose [19].…”

“…The extent of CYP3A induction was correlated with hyperforin dose. While the St. John's wort extract with the highest content of hyperforin clearly resulted in a clinically relevant CYP3A induction with 80% decrease in midazolam exposure, the products with the lowest hyperforin content resulted only in a minor 21% midazolam AUC decrease [19].…”

“…Analysis of the St. John's wort main constituents in the capsules was performed as described previously [19]. Hyperforin (adhyperforin plus hyperforin) was determined by HPLC as previously described [5].…”

“…Midazolam plasma levels were determined by GC/MS analysis with minor modifications as described previously [19,25]. GC was performed in splitless mode (60 s, then split 1:20) at an inlet temperature of 280°C using a 19091S-433 capillary column 30 m × 0.25 mm, 0.25-μm film thickness (Agilent Technologies) with helium as carrier gas at a constant flow rate of 1.0 ml/min and a temperature gradient starting at 80°C (2 min), increased at 40°C/min to 280°C, then at 25°C/min to 320°C (2 min Elimination half-life (t 1/2 ) was calculated using t 1/2 =0.693/ λz.…”

“…If this study were to show negative results, it could be presumed that less sensitive substrates would be unaffected, and no further studies would be needed [22]. In an exploratory study using midazolam as probe substrate, six St. John's wort preparations with different compositions of main constituents, especially hyperforin, have been found to induce CYP3A to different extents [19]. The extent of CYP3A induction was correlated with hyperforin dose.…”