Saint John's wort: An in vitro analysis of P‐glycoprotein induction due to extended exposure

• Published in: British journal of pharmacology 2001-12, Vol.134 (8), p.1601-1608
• Main Authors: Perloff, Michael D, Von Moltke, Lisa L, Störmer, Elke, Shader, Richard I, Greenblatt, David J
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Antidepressive Agents - administration & dosage; Antidepressive Agents - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis; Biological and medical sciences; Biological Transport, Active - drug effects; Blotting, Western; Caco-2 Cells; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance, Multiple; General pharmacology; Humans; hypericin; Hypericum - metabolism; Image Processing, Computer-Assisted; induction; intestine; Medical sciences; Microscopy, Fluorescence; Perylene - administration & dosage; Perylene - analogs & derivatives; Perylene - pharmacology; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Protein Kinase C - antagonists & inhibitors; P‐glycoprotein; Rhodamine 123 - metabolism; Ritonavir - pharmacology; Saint John's wort; Time Factors; Tumor Cells, Cultured; Verapamil - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0704399

Chronic use of Saint John's wort (SJW) has been shown to lower the bioavailability for a variety of co‐administered drugs including indinavir, cyclosporin, and digoxin. Decreases in intestinal absorption through induction of the multidrug resistance transporter, P‐glycoprotein (P‐gp), may explain decreased bioavailability. The present study characterized the response of P‐gp to chronic and acute exposure of SJW and hypericin (HYP, a presumed active moiety within SJW) in an in vitro system. Experiments were performed with 3 to 300 μg ml−1 of methanol‐extracted SJW and 0.03 to 3 μM HYP, representing low to high estimates of intestinal concentrations. In induction experiments, LS‐180 intestinal carcinoma cells were exposed for 3 days to SJW, HYP, vehicle or a positive control (ritonavir). P‐gp was quantified using Western blot analysis. P‐gp expression was strongly induced by SJW (400% increase at 300 μg ml−1) and by HYP (700% at 3 μM) in a dose‐dependent fashion. Cells chronically treated with SJW had decreased accumulation of rhodamine 123, a P‐gp substrate, that was reversed with acute verapamil, a P‐gp inhibitor. Fluorescence microscopy of intact cells validated these findings. In Caco‐2 cell monolayers, SJW and HYP caused moderate inhibition of P‐gp‐attributed transport at the maximum concentrations tested. SJW and HYP significantly induced P‐gp expression at low, clinically relevant concentrations. Similar effects occurring in vivo may explain the decreased bioavailability of P‐gp substrate drugs when co‐administered with SJW. British Journal of Pharmacology (2001) 134, 1601–1608; doi:10.1038/sj.bjp.0704399