Grapefruit juice has been found to interact with many oral drugs when taken concomi-tantly. Studies have shown that grapefruit juice inhibits cytochrome P450 3A4 (CYP3A4)- animportant enzyme involved in drug metabolism- via mechanism-based inactivation. Drug elim-ination is therefore prevented, and as a result, the bioavailability of many orally administereddrugs is substantially increased when the patient ingests grapefruit juice. The grapefruit-druginteraction may result in severe side effects, ranging from hypotension to fatal cardiac arrhyth-mias. The active ingredients in grapefruit juice are substances of the coumarin family, primarily6’7’-dihydroxybergamottin (DHB), a compound that inhibits CYP3A4 by causing irreversibleinactivation of the enzyme. A flavenoid, naringenin, is also though to play a minor role. Fur-thermore, the effects of grapefruit juice can last over 24 hours since last consumption. Becausemany drugs, including felodipine, terfenadine, cyclosporine, and saquinavir, are metabolizedby CYP3A4, it is very important to be aware of the potential side effects if grapefruit juice isconsumed while patients are on medications that are metabolized by this enzyme.Keywords: Citrus, Terfenadine, Felodipine, Cytochrome P-450Suggested Citation:Minh Chau Vu (1999) “Grapefruit Juice and Some Oral Drugs: A Bitter Combination ”,Nutrition Bytes: Vol. 5: No. 1, Article 5.
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IntroductionWhen Seldane® was first released in 1985, it immediately became a very popular allergymedicine. Seldane®, or terfenadine, was one of the first antihistamines that relieved allergy symptoms such as watery eyes, sneezing, and runny nose without causing anydrowsy side effects. However, in early 1997, the FDA recommended that it be removed from the market due to its potentially dangerous side effects affecting the heart. Therewere several documented reports of patients dying due to fatal arrhythmias. The mostsignificantly documented case was a patient who, in addition to taking terfenadine twice aday for over a year, also consumed grapefruit juice 2 to 3 times a week. On the day of hisdeath, he had taken 2 glasses of grapefruit juice before collapsing due to fatal cardiacarrhythmia. At the time, it was not known that this drug interacted with grapefruit juice, and his death was attributed to terfenadine toxicity (1). It was not until a study conducted to test the interaction between felodipine, a calciumchannel antagonist, and ethanol that by serendipity, grapefruit juice was discovered to alter drug metabolism (2). In that study, grapefruit juice was used to mask the taste ofethanol. Bailey et al. demonstrated that the combination of ethanol and felodipineresulted in orthostatic hypotension and lower blood pressure. Although the sameconcentration of felodipine was administered to each treatment arm, plasma felodipineconcentration was five-fold greater with ingestion of grapefruit juice (3). As a result, itwas proposed that grapefruit juice prevented the metabolism of felodipine by suppressingthe oxidative effects of Cytochrome P450 3A4 (CYP3A4) in the intestinal wall. MechanismFelodipine is a calcium channel blocker that is used to dilate blood vessels and decreasehypertension. Felodipine is completely absorbed in the gastrointestinal wall after oraladministration. After its absorption, it undergoes high first-pass metabolism. First passmetabolism refers to drugs that are extensively metabolized by the liver and smallintestine before reaching systemic circulation. Only drugs administered orally areaffected by first pass metabolism because they must be absorbed through thegastrointestinal wall. Therefore, the drug amount that is actually available to the body issignificantly less than the amount initially administered. Because Felodipine is usuallyhighly metabolized, its bioavailability is very low, averaging only 15%. CYP3A4 is an important enzyme involved in the metabolism of over 60 different drugs, including felodipine and other drugs that have been found to interact with grapefruitjuice. Studies have shown that grapefruit juice suppresses the activity of CYP3A4 and other CYP3A isozymes located specifically in the small intestine, allowing a greateramount of felodipine to circulate systemically. Lown et al. showed that followingconsumption of a single dose of grapefruit juice (equivalent to one 250 ml glass), therewas a decrease of immunoreactive CYP3A4 and CYP3A5 by 62% in the small intestine, but levels of CYP3A4 and CYP3A5 were unaffected in the liver and colon, respectively(3,4). When the amount of CYP3A4 mRNA was analyzed, it was discovered that themRNA concentrations were unchanged. This implied that grapefruit juice did not1Vu: Grapefruit Juice and Some Oral Drugs: A Bitter CombinationProduced by eScholarship Repository, 2006
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decrease the synthesis of CYP3A4 but rather accelerated its degradation through mechanism-based enzyme inhibition (3,10). What are some other drugs that interact with grapefruit juice?TerfenadineIn addition to affecting felodipine, grapefruit juice increases the bioavailability of manyother compounds also metabolized by CYP3A4. Grapefruit juice only affects drugs taken orally, and not those administered intravenously. Terfenadine, as was mentioned before, is a potent antihistamine that is well absorbed after oral intake and undergoes completefirst pass metabolism by CYP3A4. Levels of terfenadine are therefore rarely detected in the plasma unless there is overdose, liver disease, or inhibition of CYP3A4 metabolismvia concomitant administration of erythromycin, ketoconazole, or intraconazole (3). CYP3A4 converts terfenadine into two different metabolites: terfenadine carboxylate and azacyclonol. Terfenadine carboxylate is the active ingredient that confers antihistamineactivity and does not possess the same toxic activity as its parent compound, terfenadine. Terfenadine is a potent blocker of the delayed rectifier potassium channel in cardiacmyocytes (5). These channels are responsible for repolarizing myocytes after an action potential. Consequently, terfenadine delays the time needed for contracted myocytes to relax, thereby causing abnormal heart rhythm. A study conducted by Rau et al. showed that people given grapefruit juice in addition to terfenadine had detectable plasmaterfenadine concentrations. In addition, levels of terfenadine carboxylate plasmaconcentrations were also lower with grapefruit juice (5). Increased levels of terfenadinecan prolong QT intervals and cause ventricular arrhythmias.CyclosporineCyclosporine is an immunosuppressive drug widely used in patients who received organ transplantation. Cyclosporine levels must be very carefully monitored because of itsnarrow therapeutic window and dangerous side effects, such as nephrotoxicity, hypertension, and cerebral toxicity (6). Cyclosporine is metabolized by CYP3A in thesmall intestine and in the liver. Furthermore, grapefruit juice inhibits its metabolism onlyfor a short duration, so adverse reactions due to decreased metabolism of cyclosporinehave not been reported (6).HIV protease inhibitor- SaquinavirContrary to the toxic effects seen with felodipine and terfenadine, grapefruit juice hasbeen found to have a therapeutic effect when consumed with saquinavir, an HIV proteaseinhibitor. Saquinavir has very low bioavailability because of its first pass elimination byCYP3A4. Its low bioavailability is a major problem in serving as an anti-retroviral drugbecause patients need to consume many pills at once that are very expensive (14). However, a study showed that just one glass of grapefruit juice could increase itsbioavailability two-fold in HIV negative volunteers, suggesting that this may be one wayof increasing saquinavir bioavailability (14).2Nutrition BytesVol. 5 [1999], No. 1, Article 5http://repositories.cdlib.org/uclabiolchem/nutritionbytes/vol5/iss1/art5
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What is the active ingredient in grapefruit juice?Flavonoids are substances that are numerous in plants and citrus fruits and are able to inhibit oxidative drug metabolism (3). Unlike grapefruit juice, though, orange juice and other citrus drinks have not been found to alter drug metabolism when taken concomitantly with drugs that are metabolized by CYP3A4. This is because naringin, acertain flavonoid, is unique to grapefruit juice; orange juice contains different flavonoidsthat appear to confer no inhibitory activity (3,7,8). It was first thought that naringin wasthe compound responsible for the inhibitory effects on CYP3A4. Naringenin, which is ametabolite of naringin, is a strong suppressor of cytochrome P450 enzymes, particularlyCYP3A4 (7). However, when pure naringin was administered orally, it could notreproduce the same grapefruit effects, suggesting that some other constituent may beresponsible (8,9,10). In addition, flavonoids are not mechanism-based inactivators, and grapefruit juice inhibits CYP3A4 via this pathway.Recent studies have shown that coumarin and psoralen derivatives may be the culpritsresponsible for inhibiting first pass metabolism by CYP3A4. These compounds areknown to be mechanism-based inhibitors of cytochromes P450 (10). Psoralen and itsderivatives are abundant in grapefruit juice and are located primarily in the grapefruitpeel (7). Because these compounds are highly lipophilic, they are readily absorbed in thegastrointestinal wall and extensively metabolized. Once absorbed, psoralens seem to inhibit CYP3A4 by binding reversibly to the substrate binding site. In many cases, psoralen metabolites are active compounds that can inactivate the enzyme irreversibly. One such metabolite, 6'7'-dihydroxybergamottin (DHB), is a potent inhibitor of CYP3Aenzymes in rat liver microsomes (11). In a study conducted by Schmiedlin- Ren et al. , theauthors showed that when DHB was incubated with recombinant CYP3A4, there wasrapid degradation of the enzyme. In addition, several DHB metabolites were detected following incubation. As a result, it was proposed that DHB might be a substrate forCYP3A4, behaving also as a potent competitive inhibitor (10). The active ingredients in grapefruit juice are now attributed to psoralens, primarily DHB, with naringenin perhapscontributing a small inhibitory role (Figure 1).Because DHB is found in only certain parts of the grapefruit, the way grapefruit juice isprepared can affect the degree of drug interaction. DHB is the main componentresponsible for mediating the grapefruit effect in reconstituted frozen concentrate, themost common form of juice consumption (10). An epoxide of DHB, found only in thegrapefruit peel, is also a potent inhibitor of CYP3A4. Frozen concentrates therefore havea higher amount of active ingredient than freshly squeezed juice or the fruit itself, because the pressure exerted to prepare the frozen concentrate squeezes the grapefruitpeel containing the DHB epoxide into the juice. Grapefruit and freshly squeezed juice do not contain this epoxide, and thus have a lower amount of active ingredient (10).3Vu: Grapefruit Juice and Some Oral Drugs: A Bitter CombinationProduced by eScholarship Repository, 2006
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Figure 1. Active ingredients in grapefruit juice. (Adapted from Bailey and Fuhr)How much grapefruit juice does one need to drink before it starts to exert its effect?Studies have shown that just one glass (250 ml) of grapefruit juice is enough to preventdrug metabolism. Surprisingly, additional ingestion of grapefruit juice does not potentiateits inhibitory effect (5). In a study where two groups were given either single or doublestrength grapefruit juice, the concentration of plasma terfenadine was the same between both groups (5). Another study using grapefruit juice and felodipine produced similarresults. This suggests that "the inhibition of the pre-systemic metabolism is already fullydeveloped after a single glass of juice"; in other words, one glass of grapefruit juice isenough to cause maximum inhibition of CYP3A4 (12). Furthermore, long term ingestion of grapefruit juice does not potentiate its inhibitory effects. Lundahl et al. showed thatwhen people consumed grapefruit juice and felodipine together for 14 days straight, therewas no difference in metabolic inhibition between day 1 and day 14 (12).How long do the effects of grapefruit juice last?It only takes a few initial hours to cause rapid suppression of CYP3A4. Levels ofCYP3A4 were found to be drastically decreased within 2-4 hours after ingesting a singleglass of grapefruit juice (10). However, the effects of grapefruit juice can last over 24 hours since last consumption (13).Why does the grapefruit effect last so long? One hypothesis suggests that the activeingredient of grapefruit juice has a long half-life and is slowly absorbed from thegastrointestinal tract (13). Grapefruit juice may also cause irreversible inactivation of theenzyme. In this case, the body would have to synthesize new CYP3A4 before any drugmetabolism or elimination is to occur (13).Clinical ImplicationsBecause grapefruit juice inhibits CYP3A4, it has the potential of interacting with manydrugs whose interactions have not yet been studied. If a patient has adapted to a higherbioavailability of circulating drugs due to consumption of grapefruit juice, taking thepatient off grapefruit juice might cause an adverse effect because now the drug strength has significantly decreased. Therefore, consistency of grapefruit intake while takingmedication is very important. It is sometimes recommended that if a person has always4Nutrition BytesVol. 5 [1999], No. 1, Article 5http://repositories.cdlib.org/uclabiolchem/nutritionbytes/vol5/iss1/art5
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taken grapefruit juice with their drug, then they should continue to do so. However, if aperson has never taken grapefruit juice while on medication, then they should avoid thejuice. One problem with grapefruit juice is that the concentration of the active ingredients isextremely variable; even the way it is prepared can affect how much active component ispresent. As a result, the consequences of grapefruit-drug interaction are highlyunpredictable. Although consistency between drug and grapefruit intake is important, people who are on medication are advised to refrain from drinking grapefruit juicebecause of the unknown variability. In addition, because grapefruit juice potentiates the effect of many expensivemedications, such as cyclosporine and HIV protease inhibitors, it has been suggested thatpatients drink grapefruit juice along with their medication to reduce the amount of drugsthat that they need to take. Although this idea does sound promising, not enough research has been conducted to assess its safety.Additionally, no testing to date has verified the ingredients in the over the countersupplements, because the FDA does not regulate the supplements. For this reason, little isknown about any impurities that may cause series side effects if administered in largedoses. Finally, pyruvate is not stable as a compound and may degrade over time.Until extensive experimentation has been conducted on male and female athletes in various modes of strength and endurance exercises it is impossible to draw conclusionsabout the possible beneficial effects of pyruvate and dihydroxyacetone on athleticperformance. Although experimental results do look promising, it is important to realizethat controlled laboratory conditions are very different from real world application.To make conclusions about DHAP supplementation with regard to athletic importance, several double-blind peer-reviewed clinical trials must be conducted on male and femaleathletes in a wide range of endurance and strength exercises, using doses of thesupplement that will be used in real world application. Only after these studies have been conducted and the results verified and replicated will it be possible to accept the claimsmade by multilevel marketing distributors, health food stores, and body buildingmagazines.REFERENCES1. Spence, JD. Drug interactions with grapefruit: whose responsibility is it to warn the public? Clinical Pharmacology and Therapeutics. 1997; 61 (4): 395-400.2. Bailey, DG, Spence JD, Edgar B, Bayliff CD, Arnold JMO. Ethanol enhances thehemodynamic effects of felodipine. Clinical Investigation of Medicine . 1989; 12:357-362.3. Gailey, DG, Arnold JMO, Spence JD. Grapefruit juice- drug interactions. British Journal of Clinical Pharmacology . 1998; 46: 101-110.5Vu: Grapefruit Juice and Some Oral Drugs: A Bitter CombinationProduced by eScholarship Repository, 2006
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4. Lown KS, Bailey DG, Fontana RJ, et al. Grapefruit juice increases felodipine oralavailability in humans by decreasing intestinal CYP3A protein expression. Journal of Clinical Investigation. 1997; 99 (10): 2545-33.5. Rau SE et al. Grapefruit juice-terfenadine single-dose interaction: magnitude, mechanism, and relevance. Clinical Pharmacology and Therapeutics . 1997;61(4): 401-9.6. Adrianus AMG et al . The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients. Clinical Pharmacology and Therapeutics. 1995; 57(3): 318-24.7. Fuhr, U. Drug Interactions with Grapefruit Juice- Extent, probable mechanismand clinical relevance. Drug Safety . 1998; 18(4): 251-72.8. Ameer, B, Weintraub, RA. Drug Interactions with grapefruit juice. ClinicalPharmacokinetics . 1997; 33(2): 103-21.9. Bailey DG, Arnold JMO, Munoz C, Spence JD. Grapefruit juice-felodipineinteraction: mechanism, predictability and effect of naringin. ClinicalPharmacology Therapeutics . 1993; 53: 637-42.10. Schmiedlin-Ren,P et al. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. DrugMetabolism and Disposition . 1997; 25(11): 1228-33.11. Edwards DJ, Bellevue FH, Woster, PM. Identification of 6'7'-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. DrugMetabolism Disposition . 1996; 24: 1287-90.12. Lundahl, JUE et al. The interaction effect of grapefruit juice is maximal after thefirst glass. European Journal of Clinical Pharmacology. 1998; 54: 75-81.13. Lundahl, JUE et al. Relationship between time of intake of grapefruit juice and itseffect on pharmacokinetics and pharmacodynamics of felodipine in healthysubjects. Journal of Clinical Pharmacology . 1995; 49: 61-67.14. Kupferschmidt, H et al. Grapefruit juice enhances the bioavailability of the HIVprotease inhibitor saquinavir in man. British Journal of Clinical Pharmacology. 1998; 45 (4): 355-9.Additional Readings1. Rang, HP, Pharmacology . Churchill Livingstone, 1991.6Nutrition BytesVol. 5 [1999], No. 1, Article 5http://repositories.cdlib.org/uclabiolchem/nutritionbytes/vol5/iss1/art5
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2. Advise for the Patient- Drug Information in Lay Language . USPDI-Vol. II, 19th edition. 1999.7Vu: Grapefruit Juice and Some Oral Drugs: A Bitter CombinationProduced by eScholarship Repository, 2006
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