Volha Zabela1, Chethan Sampath2, Mouhssin Oufir3, Fahimeh Moradi-Afrapoli4, Veronika Butterweck5, Matthias Hamburger6. 1. Pharmaceutical Biology Laboratory, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland. Electronic address: volha.zabela@unibas.ch. 2. Department of Pharmaceutics, College of Pharmacy, University of Florida, 1345 Center Drive, Gainesville, FL, USA. Electronic address: chethan@ufl.edu. 3. Pharmaceutical Biology Laboratory, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland. Electronic address: mouhssin.oufir@unibas.ch. 4. Pharmaceutical Biology Laboratory, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland. 5. Department of Pharmaceutics, College of Pharmacy, University of Florida, 1345 Center Drive, Gainesville, FL, USA. Electronic address: veronika.butterweck@fhnw.ch. 6. Pharmaceutical Biology Laboratory, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland. Electronic address: matthias.hamburger@unibas.ch.
Abstract
SCOPE: 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. METHODS AND RESULTS: 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). CONCLUSION: 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. Copyright Â
SCOPE: 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. METHODS AND RESULTS: 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). CONCLUSION: 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. Copyright Â
Authors: Lucía Fernández-Del-Río; Anish Nag; Elena Gutiérrez Casado; Julia Ariza; Agape M Awad; Akil I Joseph; Ohyun Kwon; Eric Verdin; Rafael de Cabo; Claus Schneider; Jorge Z Torres; María I Burón; Catherine F Clarke; José M Villalba Journal: Free Radic Biol Med Date: 2017-06-09 Impact factor: 7.376
Authors: Danny Orabi; Lucas J Osborn; Kevin Fung; William Massey; Anthony J Horak; Federico Aucejo; Ibrahim Choucair; Beckey DeLucia; Zeneng Wang; Jan Claesen; J Mark Brown Journal: JCI Insight Date: 2021-05-10