Fifth International Congress Drug Therapy in HIV Infection 22-26 October, 2000 Glasgow, UK

ST JOHN’S WORT MODULATES BOTH EXPRESSION AND FUNCTION OF P GLYCOPROTEIN IN PERIPHERAL BLOOD LYMPHOCYTES

M. Hennessy, J. Feely, D. Kelleher, F. Mulcahy and M. Barry
Department of Pharmacology and Therapeutics, Trinity College Dublin; Department of Genito Urinary Medicine St James’ Hospital, Dublin, Ireland

Int Cong Drug Therapy HIV 2000 Oct 22-26;5:Abstract No. P275
AIDS 2000, Oct 22-26;14(Suppl. 4); S95

OBJECTIVES: St John’s Wort is a popular herbal remedy which has been shown to interact with the HIV 1 protease inhibitor indinavir resulting in a 81% decrease in the 8 h indinavir trough concentration. Indinavir is a substrate for the multi drug transporter protein P gp-170 and modulation of P glycoprotein expression and/or function by St John’s Wort may be a contributory factor in the development of this potentially harmful drug–drug interaction. We determined to evaluate the potential for St John’s Wort to alter P glycoprotein expression and function in peripheral blood lymphocytes of healthy volunteers.

METHODS: Healthy volunteers were randomized to either St John’s Wort (600 mg/d, 16 days, n = 15) or placebo (n = 5). Blood was reserved at baseline, 16 and 32 days. Peripheral blood lymphocytes were isolated by Ficoll density gradient centrifugation, fixed and permeabilised. Cells were stained with JSB1 monoclonal antibody, which reacts with a highly conserved intracellular epitope of P glycoprotein and analysed by flow cytometry. P glycoprotein drug efflux function was determined by flow cytometric analysis of intracellular Rhodamine accumulation after loading (T0) and efflux over time (T180 min), and expressed as a ratio (T180/T0). Data are expressed as mean ± sem and were analysed by non parametric analysis. A value of P < 0.05 indicates statistical significance.

RESULTS: There was no significant change in P glycoprotein expression and/ or function in the placebo group over the study period. P glycoprotein expression increased (P = 0.005) from a baseline value of 7.0 ± 0.54 MFI to a value of 29.6 ± 4.1 MFI in the active treatment group, representing a 4.5 fold increase. Sixteen days post discontinuation of St John’s Wort P gp expression had returned to baseline levels (8.5 ± 1.6 versus 7.0 ± 0.54 MFI). P glycoprotein mediated Rhodamine efflux increased (P < 0.05) following treatment with St John’s Wort compared with pre treatment functional index (0.12 ± 0.01 versus 0.19 ± 0.03), however there was no clear correlation between expression and function in either group before or after treatment.

CONCLUSIONS: Chronic administration of St John’s Wort increases expression of P glycoprotein in healthy volunteers and enhances cellular efflux of Rhodamine. This may partly explain the mechanism by which St John’s Wort reduces plasma concentrations of indinavir. Caution is recommended when St John’s Wort is co-administered with drugs known to be P glycoprotein substrates.

References

1. Piscitelli et al. Indinavir concentrations and St John's Wort. Lancet. 2000 Feb 12;355(9203):547-8.

2. Ernst E. Second thoughts about the safety of St John’s Wort. Lancet. 1999 Mar 20;353(9157):1014-5; author reply 1015-6.

Presenting author: M. Hennessy

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2000-10-22
P275

Originally published in AIDS Volume 14, Supplement 4 and hosted with permission of the publisher Lippincott Williams & Wilkins, 250 Waterloo Road, London, SE1 8RD, UK. Tel: +44 (0)20 7981 0700 Fax: +44 (0) 7981 0701

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