St. John's wort extract with a high hyperforin content does not induce P‐glycoprotein activity at the human blood–brain barrier

Abstract

St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P‐glycoprotein (P‐gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P‐gp activity at the human blood–brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)‐targeted P‐gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P‐gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3–6%) for 12–19 days (1800 mg/day), the activity of P‐gp at the BBB was assessed by means of PET imaging with the P‐gp substrate [11C]metoclopramide and the activity of peripheral P‐gp and CYPs was assessed by administering a low‐dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P‐gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P‐gp‐mediated efflux of [11C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P‐gp induction at the human BBB despite its ability to induce peripheral P‐gp and CYPs. Simultaneous intake of SJW with CNS‐targeted P‐gp substrate drugs is not expected to lead to P‐gp‐mediated drug interactions at the BBB.