title: St Johns wort increases expression of P-glycoprotein: implications for drug interactions.
abstract: OBJECTIVE
  St John's Wort (SJW) is widely used in the treatment of depression but concerns have been raised about its potential to interact with other drugs. Co-administration with SJW has resulted in significant reductions in trough plasma concentrations of indinavir and cyclosporin [1, 2]. Induction of cytochrome P450 3A4 (CYP3A4) has been implicated as the most likely interaction mechanism. However, the magnitude of the interaction seen in clinical practice is greater than that predicted by in vitro studies suggesting additional interaction mechanisms may exist. As indinavir and cyclosporin are substrates for both CYP3A4 and the multi drug transporter P-glycoprotein we hypothesized that modulation of P-glycoprotein expression and function by SJW may contribute to the development of potentially harmful drug-drug interactions.
  
  
  METHODS
  Healthy volunteers were randomized to either SJW (0.15%) 600 mg three times daily for 16 days (n = 15) or placebo (n = 7). Blood samples were obtained for P-glycoprotein expression and function at baseline, 16 and 32 days post treatment. Peripheral blood lymphocytes (PBMCs) were isolated by Ficoll density gradient centrifugation, fixed and permeabilized. Cells were stained with a P-glycoprotein specific antibody, quantified by flow cytometry and median fluorescence intensity (MFI) values obtained. Vimentin and IE (nonsense antibody) were used as controls. The presence of the MDR 1 gene product was confirmed by RT-PCR. P-glycoprotein mediated drug efflux was determined as a function of rhodamine efflux in the absence and presence of ritonavir. Data are expressed as mean +/- s.d. and were subjected to nonparametric analysis.
  
  
  RESULTS
  P-glycoprotein expression increased 4.2 fold from baseline in subjects treated with SJW (7.0 +/- 1.9 vs 29.5 +/- 14.3 (MFI); P < 0.05). There was no effect with placebo (5.1 +/- 1.3 vs 6.0 +/- 1.9 MFI). SJW increased P-glycoprotein mediated rhodamine efflux (reduced ratio) compared with baseline (0.12 +/- 0.04 vs 0.24 +/- 0.18 P < 0.05). There was no change with placebo. Ritonavir (5 microm) inhibited P-glycoprotein mediated efflux in both groups producing greater intracellular accumulation of rhodamine. However, this effect was attenuated following treatment with SJW (23.9 +/- 15.3% vs 75.4 +/- 16.4% P < 0.05).
  
  
  CONCLUSIONS
  SJW increased expression and enhanced the drug efflux function of the multi drug transporter P-glycoprotein in PBMCs of healthy volunteers. This may represent a second mechanism for the drug-herb interactions seen in clinical practice and account for the discrepancies between in vitro and in vivo data. Since P-glycoprotein and CYP3A4 have distinct though overlapping substrates, patients receiving drugs, which are P-glycoprotein substrates should be warned against self-medication with SJW as clinically significant drug interactions may occur.
authors.affiliation: Department of Pharmacology and Therapeutics, Trinity Centre for Health Sciences, St James's Hospital, Trinity College, Dublin 8, Ireland, UK.
authors.forename: Martina
authors.initials: M
authors.lastname: Hennessy
authors.forename: D
authors.initials: D
authors.lastname: Kelleher
authors.forename: J P
authors.initials: JP
authors.lastname: Spiers
authors.forename: M
authors.initials: M
authors.lastname: Barry
authors.forename: P
authors.initials: P
authors.lastname: Kavanagh
authors.forename: D
authors.initials: D
authors.lastname: Back
authors.forename: F
authors.initials: F
authors.lastname: Mulcahy
authors.forename: J
authors.initials: J
authors.lastname: Feely
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000097:blood; D000704:Analysis of Variance; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D041743:Herb-Drug Interactions; D006801:Humans; D020902:Hypericum / Q000737:chemistry*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019438:Ritonavir / Q000494:pharmacology; D016037:Single-Blind Method; D018709:Statistics, Nonparametric
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D019438:Ritonavir