Editors' pick 2009

Abstract

Much continues to be written regarding the evidence (or lack thereof ) underpinning therapeutic claims for the use of herbal medicines. Compounding the uncertainty is the potential for interactions with chemically-synthesised western medicines as exemplified by the interaction of St John's Wort (SJW) with ciclosporin that can culminate in organ rejection. These interactions with herbal medicines segue into interactions between fruits/fruit juices and drugs, with grapefruit juice (GFJ) interactions pointing up new mechanisms of drug 'absorption' and incomplete bioavailability.Whereas such interactions are predictable from in vitro data for chemically-synthesised small molecule medicines, the same cannot be said for herbal and fruitderived medicines because of the myriad of compounds that these contain. Indeed, quantitative variation in the constituents of such preparations, even between different lots of the same product, is a major unresolved problem. Hence human and not animal studies remain the primary source of information. Three recent publications in the Journal highlight new and important aspects of such interactions.Extracts from the leaves of the G.biloba tree increase the hepatic expression in rats of several CYPs, especially CYP2B. Lei and colleagues [1] investigated whether the same holds true in men using the CYP2B6 substrate bupropion. Two weeks dosing of 120 mg/day of an extract of G.biloba (provided by Now Foods, USA) had no influence on the area under the plasma concentration-time curve of bupropion and hydroxybupropion but the half life of the latter was shortened, albeit by less than 20%. Hence at least for this manufacturer's herbal preparation, no pharmacokinetic interaction with CYP2B6 substrate drugs is likely to occur in men. The possibility of a pharmacodynamic interaction (much more difficult to study) remains to be assessed.Cranberry juice inhibits CYP2C9-mediated metabolism of flurbiprofen and phenytoin in vitro and there have been case reports of clinically significant interactions with warfarin. These have not, however, been supported by human pharmacokinetic/pharmacodynamic studies. This prompted Ushijima and colleagues to investigate a potential interaction with the CYP2C9 substrate diclofenac in vitro and in vivo [2]. Cranberry juice inhibited the loss of diclofenac (rather than the formation of 4-hydroxydiclofenac) in human liver microsomes with an IC50 of 1.44% compared to the potent CYP2C9 inhibitor sulphaphenazole of 400 nM. To determine whether this would translate into a clinically significant human interaction, the researchers dosed volunteers with 180 ml twice daily of cranberry juice (containing 27% cranberry) and studied diclofenac pharmacokinetics before and after. No effect of the juice was found, presumably because whatever constituent(s) from the juice inhibited diclofenac metabolism in vitro did not achieve sufficiently high hepatic concentrations in vivo. The study highlights the need to conduct human studies to confirm conclusions based on in vitro studies.Several...