The idea that drinking a glass of fruit juice could treble the drug levels of certain drugs is a bit disconcerting. To then find out that this effect can persist for over 24 hours should be enough to make us even more concerned. This startling effect of grapefruit juice was discovered quite by chance. I suppose we can only be surprised and thankful that most people seem to survive perfectly well when they take medication in spite of these hidden perils. Some readers may find some parts of this blog post a bit technical at times, but for professional readers the extra detail is important to understand what is going on.
This interaction was discovered quite by chance in 1989 in a small study into the effect of alcohol on the absorption of Felodipine. In this study, grapefruit juice was used as a supposedly neutral ingredient to obscure the taste of alcohol, but when greatly increased drug concentrations were observed it became apparent that the grapefruit juice and not the alcohol was to blame. The significance of these results wasn’t widely publicised until several deaths were reported due to the interaction. In humans, bergamottin and dihydroxybergamottin are thought to be responsible for the “grapefruit juice effect”, in which these furanocoumarins reduce CYP3A4 mediated metabolism of certain drugs. Grapefruit juice tends to have maximum effect on orally administered drugs whose bioavailability is severely restricted by the action of this enzyme.
From a Rheumatology perspective, what should we be aware of? Of course we should be aware of the whole list of drugs (which has now grown to over 80) – but here is a list of drugs commonly encountered in the rheumatology clinic
The most important drugs to remember are those that cause a major interference with cytochrome CYP3A4, the gut enzyme that metabolises a large number of drugs.
The first of these is Ciclosporin, a drug sometimes used for treating Rheumatoid or Psoriatic arthritis. It is clear that drinking grapefruit juice causes a major increase in drug levels which can lead to serious toxicity. All patients taking this drug should be warned to avoid grapefruit and possibly Seville oranges (a common ingredient of marmalade). Avoiding grapefruit juice is mentioned in most of the patient information leaflets but we should also warn patients verbally when we prescribe it.
The second group of drugs affected by grapefruit is the statins (for lowering cholesterol). Among these, Simvastatin and Atorvastatin seem to be the main culprits – the increased drug levels can lead to an increased risk of myopathy and rhabdomyolysis (muscle injury). Pravastatin and Rosuvastatin do not seem to be affected.
It is much more difficult to get information about a number of other drugs that may in theory have a minor interaction with grapefruit juice. Among the drugs we commonly encounter in rheumatology, the following list of possible interactions can be regarded as possible but not confirmed (as far as I can establish):
Analgesics: Codeine, Tramadol, Buprenorphine, Oxycodone, Paracetamol
Others: Amitriptyline, Colchicine, Oral methylprednisolone
As far as I know, the following drugs are not significantly metabolised by CYP3A4: Methotrexate, Hydroxychloroquine, Sulfasalazine, Leflunomide, Morphine, Prednisolone. The absorption of these drugs will not be affected by grapefruit juice’s effect o CYP3A4, but that doesn’t necessarily mean that they’re in the clear…
There has been a suggestion recently that Methotrexate levels could be affected by grapefruit juice. I am not sure how much evidence there is for this, but it does not seem to be via a CYP3A4 effect.
Grapefruit juice also has been shown to reduce the plasma concentration of several drugs. This seems to be caused by the juice inhibiting the organic anion-transporting polypeptide (OATP), which assists in the uptake of drug molecules from the intestinal lumen into the enterocyte. The inhibition of OATP by grapefruit juice would reduce the absorption of drugs transported by this transporter. Orange juice and Apple juice have been found to have similar effects on the absorption of some drugs. Methotrexate levels are thought to be affected by OATP transporters, which are found in the gut, the kidneys, the liver and a few other places. The net effect of these transporters is hard to predict, as they can have competing actions – sometimes enhancing excretion and sometimes reducing it. I am not sure that there is clear evidence that fruit juices cause Methotrexate levels to go up or down significantly, but the safest thing to do would be to avoid drinking fruit juices the day or two before taking Methotrexate.
What you have read here is an over-simplification of what is actually going on – there are other transporters such as P-gp involved in drug metabolism, and we really don’t know enough about how they work and how they are affected by elements in our diet or ‘complementary’ medicines. Time for the scientists to help out – please!