Saint John's wort: an in vitro analysis of P-glycoprotein induction due to extended exposure.
1. 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. 2. 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 microg ml(-1) of methanol-extracted SJW and 0.03 to 3 microM HYP, representing low to high estimates of intestinal concentrations. 3. 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 microg ml(-1)) and by HYP (700% at 3 microM) 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. 4. 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.
Perloff
M D
MD
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts, MA 02111, USA.
von Moltke
L L
LL
Störmer
E
E
Shader
R I
RI
Greenblatt
D J
DJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000873:Anthracenes; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D015153:Blotting, Western; D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D006801:Humans; D020902:Hypericum / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D008856:Microscopy, Fluorescence; D010569:Perylene / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D020112:Rhodamine 123 / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000873:Anthracenes; D000928:Antidepressive Agents; D020112:Rhodamine 123; D010569:Perylene; C004965:hypericin; D014700:Verapamil; D011493:Protein Kinase C; D019438:Ritonavir