Watch Out, Smoothie-Interaction

4. October 2017
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A glass of grapefruit juice hasn't harmed anyone before? Incorrect. Under certain circumstances one should forego certain fruits, because the flavonoids contained can lead to interactions. Grapefruit may for instance enhance the effect of the psychopharmaceutical diazepam.

Penicillin, benzene, Teflon and LSD were created by chance. Pharmacologist Prof. David Bailey from the University of Western Ontario for example wanted to help improve the taste of a antihypertensive and in 1991 invested these efforts in grapefruit. It changed not only the taste, but also levels in the blood. Since then Bailey has not let go of this knowledge and he has investigated the effect of fruit juices on the pharmacokinetics of pharmaceutical agents.

Bailey presented the initial studies and emphasised that his findings are not limited to pomelo and grapefruit, but also apply to other sorts of fruit such as oranges and apples. Flavonoids such as naringenin, naringin and the furano­coumarin bergamottin are responsible for drug interactions. There are several different mechanisms that provoke the interaction.

1000 percent is more than a little

On the one hand the flavonoids contained in fruit inhibit so-called CYP P450 enzymes, which serve in the oxidation of many of the body’s own substances and foreign ones (eg. medications). CYP3A4 is predominantly inhibited in the intestinal wall. Therefore this interaction is only relevant when the drug is taken enterally; when taken parenterally there is no effect. If CYP3A4 is inactivated by naringenin and such substances, this reduces the presystemic first pass effect and the oral bioavailability of the active agent increases. The increase is dose-dependent and can reach well over 1,000 percent. The situation can be life threatening for the patient particularly when substances have a narrow therapeutically active range. The interactions are triggered by fruit juices, but also by fresh fruits or jam made from them. The enzyme binding is covalent and irreversible, time spacing between fruit juice intake and medication intake is therefore of not much help.

Grapefruit and St John’s wort behave inversely with respect to interactions. While grapefruit increases the level of the active substance, it is lowered by preparations derived from St John’s wort, and vice versa. The opiate antagonist naloxegol is, for example, effective in opiate-induced constipation and is metabolised by CYP3A4, grapefruit causes its blood level to rise by almost 100 percent, whereas using St John’s wort derivatives significantly reduce naloxegol’s effect. Cases of extreme tiredness accompanying grapefruit consumption may be related to prior diazepam intake, whose concentration (AUC) can rise to 320 per cent.

Transport problem with OATP

What’s more, the effect of pharmaceutical agents can be inhibited or fully eliminated without involving CYP3A4 in any way at all. One such pathway is the inhibition of the activity of transport proteins. The efflux transporter P-glycoprotein and the organic anion OAT1A2 and OAT2B1 can be involved here. Levels of the oral coagulation inhibitor apixaban can increase by nearly 100 percent through the consumption of grapefruit. Inhibiting the renal organo-anion transporter (OATP) also leads to a reduction in the elimination of certain pharmaceuticals.

If, on the other hand, the function of the OATP transporter is hindered intestinally, this can lead to a reduction or to loss of the medication’s effect. There are still many open questions with respect to the mechanisms. Moreover it is also largely unclear as to whether and how oranges, pomelos and apples interfere with pharmaceutical agents. An extensive overview on the influence of the ingredients of numerous tropical fruits is offered by Mallhi et al.

Star fruit as a star inhibitor

If one looks through the table given by Mallhi and his colleagues, one sees pineapple, pomelo, mango and lemon with quite different pharmacological eyes. Pineapple juice probably influences CYP2C9 through its bromelain content. Diclofenac, tolbutamide and coumarin derivatives are degraded through this enzyme. Lemon juice inhibits the enzymes CYP3A4, CYP2C9 and presumably also the transporting protein OATP and thus has a similar interaction spectrum to grapefruit. It would be very easy to believe that all yellow fruit juices can lead to interactions. Unfortunately, red fruits also contain flavonoids and anthocyanins.

Blueberry juice for example also interacts with CYP3A4. Cranberry juice, also used as prophylaxis of cystitis, inhibits CYP2C9 and is thus a potential interaction partner with the calcium antagonist nifedipine and anticoagulants. The star fruit (carambole) was identified as an even stronger inhibitor of CYP3A4 than the grapefruit. The Flockhart table from the University of Indiana provides an up-to-date overview of all interactions with CYP-P450.

Renin inhibition – avoid juice bars

In an extensive study by Dolton et al. the influence of grapefruit, apple and orange juice on a dozen medications was investigated by looking through databases. The renin inhibitor aliskiren was revealed to be particularly sensitive. With all three fruit juices, blood levels dropped by up to 75 percent. The betablocker atenolol in contrast does not “like” apple juice. The AUC (area under curve) fell to almost zero. Celiprolol was made practically ineffective by apple and orange juice. The antiallergenic fexofenadine does not work if the patient has consumed one of the three juices. The thyroid hormone L-thyroxine is also not compatible with grapefruit juice – blood levels were almost halved depending on dose.

The anti-arrhythmic amiodarone inhibits the sodium/potassium pump and is employed against tachycardic cardiac arrhythmia. A case history from Sheehan et al reports about a patient who experienced QT-time extensions triggered by gin tonic. The reason for this was the quinine in the bitter drink, which also interacts with a medication used against calf cramps, amiodarone.

Amiodarone has a half-life of about 100 days. In an older study by Libersa et al. changes in pharmacokinetics also occur with grapefruit juice together with an increase in blood levels.

Especially dangerous: statins

The interaction of grapefruit juice with statins is dealt with in countless studies, The blood level of lovastatin can rise by 260 per cent, that of atorvastatin by 80 percent. The peak concentration of simvastatin rises by 1200 percent, the AUC by 1340 percent.


Simvastatin concentration with grapefruit and water (mod as per Lilja J. et al.)

Statins often cause muscle pain. In addition to these instances of myalgia in rare cases muscle breakdown can also occur, the risk of which is dose-dependent. Because grapefruit is able to increase statin levels in the blood by as much as 1,200 percent statin patients should thoroughly avoid grapefruit products.

Bittersweet thrombose, plus a cup of tea and goji berries

The combination of the pill and grapefruit is also risky. Estradiol levels can increase by almost 30%, thus increasing the risk of thrombosis. Increased oestrogen levels are also associated with an increased risk of breast cancer. A study by Spencer et al. has investigated whether women who drink grapefruit juice or eat fruit are at greater risk for breast carcinomas. A freshly published study from Cirmi et al. also examined the effect of citrus juices on cancer risk and sees them as having a potential as a cancer prophylaxis.

Tea drinkers should also be careful: this is because Earl Gray tea is aromatised with essential oils of bergamot. The therein contained bergamottin is a potent inhibitor of CYP1A1. The antipsychotic clozapine for instance is metabolised through this enzyme. A cup of tea can drive up levels of the this pharmaceutical agent significantly.

Moreover the BfArM (German Federal Institute for Pharmaceuticals and Medical Products) has already had to deal with the “juice problem” and four years ago warned about interactions with preparations containing goji berry. In patients taking vitamin K antagonists, interactions may occur. In the reported cases, a significant increase in INR levels or bleeding occurred. In one female patient, the INR level rose between two monthly routine checks from 2.5 to 4.1. In another case, the INR increase was found to be 4.97. Responsibility probably lies with blockage of CYP2C9.

In a recent contribution to the discussion, the “father” of the grapefruit interactions, Bailey, however notes that the mechanisms of drug interactions are very complex and many questions still need to be clarified.

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Image copyright: Ken Hawkins, flickr / Licence: CC BY-SA

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Classic example of how medicine inhibits good nutritional habits. Did it ever occur to you that perhaps by drinking smoothies and eating lots of the produce you would like to prohibit, one could actually heal? There is lots of research proving just that. Instead of being a reductionist, one should step back from the trees and enjoy the forest. Getting away from chemicals and into real, unprocessed foods can make all the difference.

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