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.

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Although arterial stiffness is an independent cardiovascular risk factor associated with both aging and hypertension, relatively little is known regarding the structural changes in the vessel wall that occur with vessel stiffening. We determined if collagen type-I metabolism is related to arterial stiffening in both hypertensive and normotensive subjects. Arterial stiffness was assessed by aortic pulse wave velocity (PWV) and augmentation index (AIx) in 46 subjects (48.772 years, 32 hypertensives) and related to circulating markers of collagen type-I turnover. Collagen synthesis was assessed by the measurement of carboxy-terminal peptide of procollagen type-I (PIP) and collagen degradation by the measurement of carboxy-terminal telopeptide of collagen type-I (ICTP), by quantitative immunoassay. Matrix metalloproteinase-1 (MMP-1) and the tissue inhibitor of metalloproteinase-1 (TIMP-1) were also quantified by immunoassay. The ratio of collagen type-I synthesis to degradation was negatively correlated with both PWV (Po0.05) and AIx (Po0.05), whereas plasma MMP-1 levels displayed a positive correlation with both PWV (Po0.01) and AIx (Po0.01), after adjustment for age and mean arterial pressure. The relationship between collagen type-I turnover and arterial stiffness was similar in both the normotensive and hypertensive subjects. Although circulating markers of collagen synthesis were increased in the hypertensive subjects, this was not related to arterial stiffness. Collagen type-I degradation is increased in relation to collagen type-I synthesis in subjects with stiffer arteries. Matrix metalloproteinase-1, the enzyme responsible for collagen type-I degradation, is positively related to both large elastic and muscular artery stiffness in normotensive and hypertensive subjects.