The first clinically relevant reports of preparations of St. John's wort (SJW), a herbal medicine with anti‐depressant effects, interacting with other drugs, altering their bioavailability and efficacy, were published about 20 years ago. In 2000, a pharmacokinetic interaction between SJW and cyclosporine caused acute rejection in two heart transplant patients. Since then, subsequent research has shown that SJW altered the pharmacokinetics of drugs such as digoxin, tacrolimus, indinavir, warfarin, alprazolam, simvastatin, or oral contraceptives. These interactions were caused by pregnane‐X‐receptor (PXR) activation. Preparations of SJW are potent activators of PXR and hence inducers of cytochrome P450 enzymes (most importantly CYP3A4) and P‐glycoprotein. The degree of CYP3A4 induction correlates significantly with the hyperforin content in the preparation. Twenty years after the first occurrence of clinically relevant pharmacokinetic drug interactions with SJW, this review revisits the current knowledge of the mechanisms of action and on how pharmacokinetic drug interactions with SJW could be avoided.Linked Articles: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc

The development of a new drug is generally marked by a number of preclinical investigations in a sequential order with regard to contents and logic. However, ethnopharmacology often uses the “reverse pharmacology” approach, which is based on anecdotal therapeutic effects of plants in ancient texts or based on the empirical knowledge of traditional healers. While this approach could successfully lead to new therapeutic applications by using sophisticated techniques and appropriate bioassays in a logical order, unfortunately there is an exponentially increasing number of reports of pharmacological effects of botanical extracts with insignificant bioactivities obtained in often irrelevant in vitro bioassays. The interpretation based on in vitro data can only be misleading since the pharmacokinetic properties of a compound are ignored, unacceptable high dosages of extracts are tested, or metabolism to inactive metabolites is not considered. Further, many natural products are prodrugs that need to be metabolized in vivo by the intestinal microflora or by mammalian phase I/II metabolism. Frequently, attempts are made to master poor pharmacokinetics by administering the extract intraperitoneally or intravenously, clearly moving away from the traditional oral application. In this review article, it is proposed that preclinical testing strategies of botanicals should start with the in vivo examination of extracts in relevant animal models to substantiate the ethnopharmacological/ethnopharmaceutical use, followed by bioguided fractionation processes using an adequate in vitro model, further followed by pharmacokinetic studies and final in vivo testing of isolated compounds. With our article we would like to encourage authors, reviewers and editors to implement this strategy for the design of experiments and for the reviewing and editing process of manuscripts.

Kaempferol is a major flavonoid in the human diet and in medicinal plants. The compound exerts anxiolytic activity when administered orally in mice, while no behavioural changes were observed upon intraperitoneal administration, or upon oral administration in gut sterilized animals. 4-Hydroxyphenylacetic acid (4-HPAA), which possesses anxiolytic effects when administered intraperitoneally, is a major intestinal metabolite of kaempferol. Pharmacokinetic properties of the compounds are currently not clear. UHPLC-MS/MS methods were validated to support pharmacokinetic studies of kaempferol and 4-HPAA in rats. Non-compartmental and compartmental analyses were performed. After intravenous administration, kaempferol followed a one-compartment model, with a rapid clearance (4.40-6.44l/h/kg) and an extremely short half-life of 2.93-3.79min. After oral gavage it was not possible to obtain full plasma concentration-time profiles of kaempferol. Pharmacokinetics of 4-HPAA was characterized by a two-compartment model, consisting of a quick distribution phase (half-life 3.04-6.20min) followed by a fast elimination phase (half-life 19.3-21.1min). Plasma exposure of kaempferol is limited by poor oral bioavailability and extensive metabolism. Both compounds are rapidly eliminated, so that effective concentrations at the site of action do not appear to be reached. At present, it is not clear how the anxiolytic-like effects reported for the compounds can be explained.

Extracts prepared from the leaves of Phyllostachys edulis (bamboo) have received attention in pharmacological research due to their potent antitumor, anti-inflammatory, antimicrobial, and anti-ulcerogenic activities. In this study, anti-inflammatory effects of a bamboo leaf extract on tumor necrosis factor alpha-induced overproduction of interleukin 8, vascular endothelial growth factor, and interleukin 6 in immortalized human keratinocytes were investigated for the first time. In addition, wound-healing effects were evaluated in 3T3-swiss albino mouse fibroblasts. Bamboo leaf extract and isoorientin inhibited the tumor necrosis factor alpha-induced release of interleukin 8 and vascular endothelial growth factor. Furthermore, isoorientin dose-dependently reduced levels of interleukin 6 in tumor necrosis factor alpha-α-treated immortalized human keratinocytes cells. Wound healing was evaluated using a modification of the classical scratch assay. For evaluation of the wound gap, a new computerized method based on time-lapse microscopy was developed. It was shown that bamboo leaf extract (10 µg/mL) improved wound closure by 28 % (12 h) and 54 % (24 h), respectively. In concentrations of 50 µg/mL and above, bamboo leaf extract inhibited cell migration without affecting cell viability. Isoorientin (10 µM) improved wound closure by 29 % (12 h) and 56 % (24 h), respectively. Comparable to bamboo leaf extract, higher concentrations of isoorientin prevented cell migration. It is suggested that bamboo leaf extract as well as isoorientin have a dual activity – in higher doses, they show anti-inflammatory effects, and in lower concentrations, they exert anti-angiogenic activities.