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What is Grapefruit?
Grapefruit, a relative newcomer to citrus clan, has a fascinating history. It is a large orange berry with a thick rind. It is the belief of the most botanists that grapefruit is a naturally occurring accidental hybrid between pomelo and orange. It is believed that, although its appearance is very much different from an ordinary grape, the name ‘grapefruit’ was used because they grow in clusters, and these clusters may seem as large yellow grapes.
The original belief was that, the grape fruit is a kind of a pomelo. (1) But in 1837, James Macfayden, separated grapefruit from pomelo, in his Flora of Jamaica, giving it a botanical name, Citrus paradisi. After its hybrid nature was genetically identified, the botanical name was altered to Citrus X paradisi. (1)
Grapefruit, like most of the other citrus fruits, is a great source of vitamin C, which helps the immune system. It is advantageous for the fight against, from simple cold to, asthma, rheumatoid fever, osteoarthritis, cancer, heart disease and stroke. (2)
Lycopene, which gives grapefruit its red and pink colors, is a carotenoid phytonutrient, with high anti-tumor ability. Also lycopene has the highest capacity among the common dietary carotenoids to fight free radicals. (2)
According to the availability of the content of phenolic compounds in the grapefruit juice, it is ranked among the highest in food products of antioxidant activity. (2)
Limonoids, another phytonutrient in grapefruit, promotes the formation of glutathione-S-transferase, thus minimizing the tumor formation. Pectins, a form of soluble fiber in grapefruit is useful against the progression of atherosclerosis. (2)
Also, the grapefruit juice increases urinary pH value and citric acid excretion, and significantly reduces the formation of calcium oxalate stones, thus minimizing kidney stone formation. (2)
Naringenin, a flavonoid concentrated in grapefruit, helps to repair damaged DNA, especially in human prostate cancer cells. 8-oxoguanine-DNA glycosylase and DNA polymerase beta, enzymes are induced by Naringenin, which are useful in DNA base excision repair pathway. (2)
Although the nutritional value of grapefruit is highly commended and proved, around a decade ago, scientists found that the availability of oral drugs can be severely reduced by grapefruit food products, especially grapefruit juice. The cytochrome P-450 3A4 system, in the intestine, which is facilitates the first pass metabolism in many drugs, can be inhibited by grapefruit. Also in the brush border of intestinal wall, there are P-glycoprotein pumps. They transport many of the substances used by cytochrome P-450 3A4. This system is also inhibited by grapefruit. Inhibition of both these systems can be dangerous. Because of these, knowledge and awareness of these interactions is massively important. These interactions can lead to severe effects and these interactions can occur very commonly as most of the times, both the drugs and grapefruit food products are used together at breakfast. (3)
Mechanism of interaction
Cytochrome 3A4 is a member of cytochrome P-450 enzyme system. In the endoplasmic reticulum of cells all over the body, it can be found. It is a heme-containing large multigene family. As oxidative bio-transformation of different exogenous and endogenous substances occurs in liver and intestinal wall, cytochrome P-450 is abundant in those places. In the apical brush border of enterocytes, P-glycoprotein can be found. It is a membrane transporter and a member of adenosine triphosphate binding cassette (ABC).
Once lipophilic drug is taken into the enterocytes, it is pumped back into the lumen by P-glycoprotein or metabolized by cytochrome P-450 3A4. These actions limit the oral delivery of many drugs. With the intake of grapefruit juice, cytochrome P-450 system is inhibited, thus pre-systemic metabolism of drug is decreased and bioavailability of the drug increase. (4)
Grapefruit juice causes massive reduction in translation of these enzymes from its m-RNA. However the transcription of m-RNA from DNA is not affected. Grapefruit also promotes the deterioration of these enzymes. These actions together, massively decline the cytochrome P-450 activity in a quick and irreversible manner. A decline of 47% of total levels of cytochrome P-450 3A4 levels can be seen within the four hours of grapefruit juice ingestion. With this decrease, increased bioavailability of the drug can be maintained for about a day. Even after that, for some time, 30% of its effect is still there. (5-7)
Some studies indicate that effect on grapefruit juice on cytochrome p-450 3A4 system and P-glycoprotein system are controversial. Means grapefruit juice can activate the P-glycoprotein pumps in vitro in a way (9). This could result in massive efflux of drugs back into the lumen. This is believed to be the cause for diminished bioavailability of some particular substrates, or sometimes this can neutralize the effect of reduced cytochrome P-450 3A4 activity due to ingestion of grapefruit juice.
However Digoxin, a prototypical P-glycoprotein substrate, is found as one of the substrates in P-glycoprotein pump, which is not affected by grapefruit juice (8, 10).
By both inhibition of function and, down-regulation, grapefruit juice inhibits the function of P-glycoprotein pumps. Example: increased bioavailability of cyclosporine with the grapefruit juice. This is believed to be a result of P-glycoprotein inhibition, other than cytochrome P-450 3A4, since the increase of bioavailability, produced by reduced enterocyte cytochrome P-450 3A4 concentrations, are tend to differ than the obtained results (8). MRP2 (multi-drug resistant protein 2) an associated P-glycoprotein efflux protein, has also shown its inhibition of action, with the ingestion of grapefruit juice (11).
In spite of all the acquired knowledge, researchers still further investigate the grapefruit and drug interactions. In vivo effect of grapefruit juice on P-glycoprotein is an area believed to be needed to investigate further more.
OATPs or organic anion-transporting polypeptides also said to be potently inhibited by grapefruit juice. In the small intestine, they are involved in the process of apical to basal transport of drugs (8, 10, and 12).
The knowledge and conclusions obtained with the studies carried out in vitro cytochrome P-450 3A4 inhibition by grapefruit, the likelihood of these interactions happening in a natural way (the ingestion of grapefruit food products) can be predicted. It is also believed that the reported ethnic differences and the activity of the cytochrome P-450 3A4 could be because of the dietary differences, such as consumption of grapefruit.
All in all, because of the potential of grapefruit and grapefruit related food items to interact with drugs, intake of grapefruit should be carefully monitored, in order to maintain necessary drug concentrations within the body of a patient, within the therapeutic windows.
Another aspect that the researchers are still thoroughly studying on is knowledge about active constituents in grapefruit juice in the molecular level, which can interfere and act on P-glycoprotein pumps and cytochrome P-450 systems. Although these studies are not extensively studied or completely proven, they indicate various molecules that take part in the drug interaction process. Flavonoid glycosides such as naringin, naringinin, hesperidin, neohespiridin, narirutin, quercetin, and didymin are some of substances responsible. Also, sesquiterpen and furanocoumarins (such as 6,7-dihydroxybergamottin) are also responsible (3, 14-16).
Naringin is the most abundant flavonoid contained in the grapefruit juice. Also the flavonoids in the grapefruit exist as glycosides. After ingestion, the actions of intestinal flora convert these to sugars and aglycones. These compounds can inhibit the cytochrome P-450 enzymes. Theoretically, it is believed that electron rich polyphenolic nature of these compounds is responsible for that.
Most studies show the in vitro effect of these compounds on cytochrome P-450 enzyme system. But in vivo, researchers have not yet completely proven or identified their effects on cytochrome enzyme system (17). Naringinin, which is a metabolite of naringin, has a higher activity in vitro, although naringin has no visible effect. This leads to a complication and some suspicion among researchers that flavonoids may not be the main active substance in grapefruit, which is responsible for the whole drug interaction dilemma. Even though with all these debates, due to very high concentration of these compounds in grapefruit juice and the fact naringin is present only in grapefruit among the fruits in citrus clan, quest for flavonoids still continues.
Recent researchers are mostly focusing on furanocoumarins. Main furanocoumarins are bergomottin and its derivative 6,7-dihydroxybergomottin(DHB)(18). Debates still going on about the extent of effect these compounds on interaction mechanism certain studies have shown that DHB and, to an average amount bergamottin are vital contributors of grapefruit-drug interaction process (18, 19). In one particular study, furanocoumarins, DHB and four others, mixed and tested. The inhibitory potency on cytochrome enzyme systems declinedeven when any one of these compounds taken out from the mixture, not just DHB. That created a complication. There are even studies supporting that perhaps DHB and bergomattin may not be the primary compounds in the inhibition process (20). With all these facts this idea also still in the process of intense research and suspicion.
Amiodarone and anti-hypertensive drugs
1,4-dihydropyridine calcium antagonists are used mostly for patients with angina pectoris and also for patients with essential hypertension. They are lipid soluble drugs, metabolized by cytochrome P-450 3A4 in vivo, and grapefruit juice can affect its bioavailability. Intensive study and research began with the effects of grapefruit juice with felodipine, another calcium channel blocker and an anti-hypertensive drug. It was found that when grapefruit juice is ingested, oral bioavailability of these drugs can increase by 112% (21). Furthermore it demonstrates that intra-venous pharmacokinetics of felodipine remains without a significant change with the grapefruit juice ingestion (21). Also the interaction frequency gradually increases with the increased grapefruit juice ingestion. Because of these reasons, it is recommended that interval of 2-3 days between administration of felodipine and ingestion of grapefruit juice. The elderly specially should be warned about this situation.
Amioderone is used for cardiac arrhythmias. It is converted into N-desethylamioderone by cytochrome P-450 3A4. With the ingestion and interaction with grapefruit juice, N-desethyl amioderone production inhibits almost completely, with an overall decline in side effects produced by amiodarone (8).
Furthermore benzothiazepine calcium channel antagonist diltiazem, nisoldipine, verapamil, ACE inhibitors like enalapril and aptopril also said to have effect with grapefruit juice interaction.
Benzodiazepines and CNS drugs
Midazolam is a drug of benzodiazepine class used for acute seizures for inducing sedation and in insomnia. Certain studies have proven that grapefruit juice has a great effect on first-pass metabolism, which reduces the metabolism efficiency badly and increase its bioavailability (22). Clinical importance is that especially for the patients with cirrhosis of the liver, intestine metabolism of cytochrome P-450 3A4 is vital. So the ingestion of grapefruit juice has to be avoided. Another use of midazolam is in pediatric dentistry. Oral midazolam is very commonly used for this. There have been incidents that because of the bitter taste acquired with the administration of oral midazolam, patients tend to take sweetened food items, sometimes grapefruit. If grapefruit was taken in after administration of oral midazolam, blood plasma midazolam levels can increase and patient may tend to have exaggerated seduction time. Triazolamand clozapine are some other drugs that can also affect.
Indinavir is commonly used to treat HIV in highly active antiretroviral therapy. It is a protease inhibitor. There are reports showing that ingestion of grapefruit juice can delay indinavir absorption with the increase of gastric pH, but it does not affect systemic bioavailability (23). It is believed, because primary metabolism may not take place in the intestine.
Saquinavir is also another drug used for patients with HIV. It is also a protease inhibitor. It is shown that the ingestion of grapefruit juice can increase the bioavailability of saquinavir (24). Although it increased the bioavailability, the clearance of the drug won’t change. This could be an indication that inhibition of cytochrome P-450 3A4 is affected. Theoretically, because of the dose dependent nature of the saquinavir, it is possible that effectiveness can increase with the inhibition of cytochrome P-450 3A4.
Artemether an anti-malarial drug, also shown its increasing oral bioavailability, when grapefruit juice is ingested. But its time dependent reduction of bioavailability does not affect by grapefruit (25). This could indicate the importance of cytochrome P-450 3A4 in the pre-systemic metabolism.
Quinine, a natural drug used in broad range of aspects, seemed to be does not affected by grapefruit juice. It is because it is primarily metabolized in the liver. (Where inhibition of cytochrome P-450 3A4 with grapefruit mainly effect on the gut)(8) Its low clearance is also helpful for this.
Furthermore in antibiotics, clarithromycin, show increased time for reach for its peak concentration, but pharmacokinetics seemed to be unaffected (26). While abendazole, an anti-parasitic, shows an increased bioavailability with the ingestion of grapefruit juice (27).
Cyclosporine is a widely used immunosuppressant drugs, used in organ transplants. Studies have shown that cyclosporine and its metabolites both show rapid increase in their concentrations in plasma, when grapefruit juice was administered (28).
Anti-histamines and serotonin analogues
Cisapride is a drug that increases the motility of the upper GI tract. It is a serotonin receptor agonist. Studies have shown that cisapride systemic bioavailability gradually increases with the administration of grapefruit juice (29), because of the inhibition of cytochrome P-450 3A4. Therefore it’s advisable, that the patients who are taking cisapride, especially with a risk of cardiac arrhythmias, should avoid drinking grapefruit juice.
Terfenadine, anti-histamine, also show increased system bioavailability when grapefruit juice is taken in (30). This also play an important role, because in an electrocardiogram, increased systemic levels of terfenadine can prolong the QT interval.
Statins and cholesterol-lowering drugs
Simvastatin, a cholesterol lowering drug, also shown increased serum concentrations when grapefruit juice is taken (31). Also its active metabolite simvastatin acid levels and HMG-CoA reductase inhibitors also increase. Active metabolites of the grapefruit juice, Bergamottin and Naringenin are said to be responsible for this. It is also carried out from the inhibition of cytochrome P-450 3A4 and thus limiting the first pass metabolism in small intestine.
Lovastatin, another cholesterol reducing drug said to have same effects as simvastatin, when the grapefruit juice is administered. Serum concentrations of lovastatin and its active metabolite lovastatin acid seem to be elevated. By the same mechanism, prevention of first pass metabolism in the small intestine by inhibiting cytochrome P-450 3A4.
Because of the vast difference of effects given by grapefruit-drug interactions, and its effects on pharmacokinetics, physicians should be vigilant about the whole procedure. And also warn their patients about the possible consequences which can happen in a drug-grapefruit interaction. Patient-to-patient variability, mostly the age of the patient, should be thoroughly remembered. And the elderly should be warned especially as they are more prone to the grapefruit-drug interactions (8). Also the knowledge about these interactions can be used for the advantage of the physician. Example: to lower the dosage. Still, because all these are mostly in a research level and safe procedures should always be followed as patients safety is the top priority.