How to make grapefruit juice

Grapefruit and medicinal products

Interactionsby Petra Zagermann-Muncke, Eschborn

There are repeated reports in the public media about the interactions between grapefruit juice and pharmaceuticals - unfortunately often inaccurate. The article presents the facts about the mechanism of grapefruit interactions and derives specific recommendations for practice.

The grapefruit, Citrus paradisi L., influences the pharmacokinetics of numerous medicinal substances. The most important mechanism is the irreversible inhibition of the cytochrome P450 isoenzyme CYP3A4 in the intestinal wall. This enzyme catalyzes the oxidative metabolism of many drugs when they are absorbed through the intestinal mucosa and is therefore responsible for the intestinal or presystemic first-pass effect. If the enzyme is inactivated by grapefruit juice, this reduces the intestinal first-pass effect and the bioavailability of the drug increases.

Suicide inhibition

In a study with healthy volunteers, the amount of CYP3A4 protein in the mucous membrane of the small intestine was reduced by about half after ingestion of 300 ml grapefruit juice daily for a period of seven days. However, since no decreased levels of CYP3A4 mRNA were found, grapefruit seems to accelerate the proteolysis of CYP3A4. Presumably, grapefruit ingredients or their metabolites bind covalently and irreversibly to CYP3A4 and the isoenzyme inactivated in this way is broken down more quickly. This process, known as suicide inhibition, is already fully active four hours after ingesting grapefruit and lasts longer than 24 hours.

 

Practical tips for dealing with grapefruit interactions
  • Grapefruit only increases bioavailability if the drug concerned is administered orally, because the interaction occurs during absorption through the intestinal mucosa.
  • Fruits, juice and other preparations of grapefruit are equally affected, not just grapefruit juice, which is explicitly mentioned in most publications and with which most of the studies were carried out.
  • Patients should avoid grapefruit and grapefruit juice altogether when taking the affected drugs. The interaction will not be avoided if only concomitant ingestion is avoided, because grapefruit induces an irreversible inhibition of CYP3A4, which can last for 24 hours to several days. Since grapefruits are not a staple food in Germany, you can do without it without any problems.
  • An amount of grapefruit or grapefruit juice that is certain not to cause an interaction cannot be specified. The recommendation to avoid only "large amounts" of grapefruit lacks a scientific basis and is also not practical.
  • Other citrus fruits have hardly been investigated for enzyme-inhibiting effects, but have not been noticed in this regard either. Orange juice does not appear to inhibit the oxidative metabolism of drugs. However, there is evidence of this for other citrus fruits.

  

There is a wide range of expression of CYP3A4 in the population. The activity can vary by a factor of 8 between individuals. The greater the activity of CYP3A4 in a patient, the more noticeable the effect of CYP3A4 inhibitors. This is reflected in large inter-individual differences in grapefruit interactions. Some research suggests that grapefruit also affects the activity of transport proteins such as P-glycoprotein and organic anion transport polypeptides (OATP).

Ingredients and quantities

Interactions were found with grapefruit juice and fresh fruits alike. It is still unclear which ingredients of the grapefruit are responsible for the interactions. Flavonoids such as naringenin / naringin, which occurs mainly in grapefruit, and the furocoumarin 6 ‘, 7‘-dihydroxybergamottin are" suspected ". These compounds are not found in orange juice with which no interactions have been found. However, in a few cases, interactions with bitter oranges, including bitter or Seville oranges (Citrus aurantium), and pomelo (Citrus maxima) have been reported.

Even a glass of grapefruit juice (200 ml) can cause a clinically relevant interaction. Commercially available double-concentrated grapefruit juices from the USA did not produce a stronger effect. Since it is not certain which ingredients trigger the interaction and how much their content varies in fresh fruits as well as in commercial juices, no consumption amount can currently be stated that does not have an interaction to be expected.

Which are clinically relevant

The consumption of grapefruit or grapefruit juice during therapy with certain medicinal substances (table) can increase their plasma concentration to very different degrees. Because of the large inter-individual differences in these interactions, it is difficult to predict which patients will be affected by a clinically relevant interaction. The extent to which the interaction affects the patient depends not only on the extent to which the bioavailability of the drug increases, but also on its therapeutic index and toxicity. For example, the therapeutic range of the immunosuppressant cyclosporine is narrow and a relatively small increase in bioavailability can cause undesirable effects on the kidneys, liver and nerves. In contrast, the therapeutic range of the tranquilizer buspirone or the calcium antagonists of the dihydropyridine type is greater and the effects of increased bioavailability are not as serious.

 

Table: Interactions with grapefruit in the ABDA database (as of June 2005)

Affected substancesFinished medicinal products (Examples ®)Possible effects   enhanced effect Bexarotene Targretin concentration-dependent effects intensified Buspirone Bespar concentration-dependent effects intensified (dizziness, tiredness) Cholesterol Synthesis Inhibitors
Atorvastatin, Lovastatin, Simvastatin Sortis, Mevinacor, Zocor increased risk of myopathy cisapride not currently available in Germany increased risk of ventricular tachycardia (QT time prolongation) Darifenacin Emselex increased concentration-dependent effects (anticholinergic effects) Immunosuppressants
Ciclosporin, Everolimus, Sirolimus, Tacrolimus Sandimmun, Certican, Rapamune, Prograf increased risk of nephrotoxic, neurotoxic and hepatotoxic effects nifedipine and derivatives
(except amlodipine, isradipine) Adalat
(except Norvasc, Vascal) increased blood pressure drop, flush, headache Phosphodiesterase 5 inhibitors
Sildenafil, Tadalafil, Vardenafil Viagra, Cialis, Levitra Drop in blood pressure, blurred vision, painful permanent erections Pimozid Orap concentration-dependent effects increased (QT time prolongation) Quetiapine Seroquel concentration-dependent effects increased terfenadine terfenadine increased risk of ventricular tachycardia and analogous vermin prolongation Isoptin increased cardiovascular effects (drop in blood pressure, cardiac arrhythmias) Zolpidem Stilnox increased concentration-dependent effects (central depressant) diminished effectNitrogen mustard derivatives
Cyclophosphamide, Ifosfamide Endoxan, Holoxan decreased cytostatic effectiveness

 

A number of other statistically significant interactions with grapefruit juice have been described in the literature, but these are not considered to be clinically relevant due to the small extent and the wide therapeutic range of the drugs and their low toxicity. Some HIV protease inhibitors, estrogens, and benzodiazepines belong to this class.

Note the interaction of grapefruit with the nitrogen mustard derivatives cyclophosphamide and ifosfamide. The two active ingredients are prodrugs that are hydroxylated by CYP3A4 and thus bioactivated. Their bioactivation can be restricted by grapefruit, so that, in contrast to the other interactions, a reduced effectiveness must be expected in this case.

Do not use interaction therapeutically

With the administration of grapefruit juice an attempt was made to increase the bioavailability of the immunosuppressant cyclosporine and thus to save drugs. In view of the large differences in CYP3A4 activity in the population and the lack of knowledge about the responsible ingredients, such a procedure cannot be recommended, since the extent of the increase in bioavailability cannot be calculated.

 

literature

  • Bailey, D.G. et al .: Interactions between grapefruit juice and cardiovascular drugs. At the. J. Cardiovasc. 4 (2004) 281-297.
  • Kane, G.C. et al .: Drug-grapefruit juice interactions Mayo Clin. Proc. 75 (2000) 933-942.
  • Wunderer, H .: Interactions: Not every drug can tolerate grapefruit juice. Pharm. Ztg. 143 (1998) 2467-2478.

 

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