St John's Wort increases expression of P‐glycoprotein: Implications for drug interactions

Abstract

Aims 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 signi®cant 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, ®xed and permeabilized. Cells were stained with a P-glycoprotein speci®c antibody, quanti®ed by¯ow cytometry and median¯uorescence intensity (MFI) values obtained. Vimentin and IE (nonsense antibody) were used as controls. The presence of the MDR 1 gene product was con®rmed by RT-PCR. P-glycoprotein mediated drug ef¯ux was determined as a function of rhodamine ef¯ux in the absence and presence of ritonavir. Data are expressed as meants.d. and were subjected to nonparametric analysis. Results P-glycoprotein expression increased 4.2 fold from baseline in subjects treated with SJW (7.0t1.9 vs 29.5t14.3 (MFI); P<0.05). There was no effect with placebo (5.1t1.3 vs 6.0t1.9 MFI). SJW increased P-glycoprotein mediated rhodamine ef¯ux (reduced ratio) compared with baseline (0.12t0.04 vs 0.24t0.18 P<0.05).There was no change with placebo. Ritonavir (5 mM) inhibited P-glycoprotein mediated ef¯ux in both groups producing greater intracellular accumulation of rhodamine. However, this effect was attenuated following treatment with SJW (23.9t15.3% vs 75.4t16.4% P<0.05). Conclusions SJW increased expression and enhanced the drug ef¯ux 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 signi®cant drug interactions may occur.

Drug Interactions Between Antiretroviral Drugs and Comedicated Agents

“…[233] Induction of CYP3A and/or P-glycoprotein was suggested in the interaction of St John's wort and IDV, in which St John's wort reduced the AUC of IDV by 57% (table III). [208,234] That herbal agents are not as harmless as generally thought is also illustrated by clinically important interactions observed with garlic supplements and grapefruit juice (table III). In a study in healthy volunteers, garlic supplements administered twice daily for 20 days resulted in a 51% reduction in the AUC of SQV, probably by induction of CYP enzymes.…”

Improving the oral bioavailability of beneficial polyphenols through designed synergies

“…Using purified polyphenols on Pgp overexpressing cells in vitro, Patel et al [59] showed that quercetin, hypericin and kaempferol were able to increase the cellular uptake of ritonavir by five-to eightfold. It is also interesting to note that in vitro assays or short-term exposure to these polyphenols in vivo appears to inhibit the action of efflux pumps and increase substrate bioavailability, whilst chronic exposure in healthy volunteers actually increases the expression of Pgp and, hence, reduces the bioavailability of efflux pump substrate drugs [14,27].…”

“…P-glycoprotein (Pgp/ MDR1), MRP2 and BCRP are localised in the apical membrane, effluxing compounds back in to the gut lumen; whereas MRP1, 3 and 5 are localised in the basolateral membranes pumping substrates in to the blood stream. MRP4 is present in both the apical and basolateral membranes of gut epithelia [6] chronic exposure to some polyphenol efflux pump inhibitors may actually increase transporter expression over time [14,27].…”

Interações medicamentosas de fitoterápicos e fármacos: Hypericum perforatum e Piper methysticum

“…Pesquisadores da Universidade de Zurique (Suíça) mostraram que a erva interfere no efeito imunossupressor da ciclosporina, utilizado na prevenção de rejeição a órgãos transplantados, (Baede Van Dijk et al, 2000;Breidenbach et al, 2000;Moore et al, 2000;Ruschitzka, et al 2000;Moschella e Jaber, 2001;Hennessy et al, 2002). A queda nos níveis séricos de ciclosporina e a rejeição de órgãos ou tecidos transplantados, podem ocorrer em poucas semanas após o uso concomitante de extrato de hipérico.…”