Medicinal importance of grapefruit juice and its interaction with various drugs

1475-2891-6-33 1475-2891 Review Medicinal importance of grapefruit juice and its interaction with various drugs Kiani Jawad jawad.kiani@gmail.com Imam Z Sardar zakariya.imam@gmail.com

Medical College, Aga Khan University, Stadium Road, Karachi, Pakistan

Nutrition Journal 1475-2891 2007 6 1 33 http://www.nutritionj.com/content/6/1/33 17971226 10.1186/1475-2891-6-33 27 6 2007 30 10 2007 30 10 2007 2007 Kiani and Imam; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Grapefruit juice is consumed widely in today's health conscious world as a protector against cardiovascular diseases and cancers. It has however, been found to be an inhibitor of the intestinal cytochrome P – 450 3A4 system, which is responsible for the first pass metabolism of many drugs. The P – glycoprotein pump, found in the brush border of the intestinal wall which transports many of these cytochrome P – 450 3A4 substrates, has also been implicated to be inhibited by grapefruit juice. By inhibiting these enzyme systems, grapefruit juice alters the pharmacokinetics of a variety of medications, leading to elevation of their serum concentrations. Most notable are its effects on the calcium channel antagonist and the statin group of drugs. In the case of many drugs, the increased serum concentration has been found to be associated with increased frequency of dose dependent adverse effects. In this review, we have discussed the phytochemistry of grapefruit juice, the various drugs involved in the drug – grapefruit juice eraction with their mechanisms of action and have presented the clinical implications of these interactions.

Introduction

The grapefruit, thought to be a cross between an orange and a shaddock, was developed in the West Indies in the early 1700s and first introduced to Florida in the 1820s. Since the early part of the 20th century, mutant strains of white grapefruit have appeared with pink to slightly reddish colour, and have been propagated by citriculturists into several strains of grapefruit. The three major types of grapefruit that exist today are white, pink/red and ruby/rio red varieties. Grapefruit juice combines the sweet and tangy flavour of the orange and shaddock and also provides up to 69% of the RDA for vitamin C along with as many as 250 mg of Potassium 1.

However, the wide consumption of grapefruit juice cannot entirely be attributed to its taste, and nutritive value. In fact, much of the enthusiasm in its use stems from medical research that has suggested that grapefruit juice reduces atherosclerotic plaque formation 2 and inhibits breast cancer cell proliferation and mammary cell tumorigenesis 34. Traditionally grapefruit juice has been found to contain antioxidant, antinitrosaminic, antiseptic, aperitif, cardiotonic, detoxicant, hypocholesterolemic, sedative and stomachic activities. In the light of its above activities, it has been traditionally indicated throughout time for anorexia, bacteria, benign prostatic hypertrophy, cancers (breast, colon, prostate, lung, skin and throat), candida, cold, diabetes, dysuria, high cholesterol, infection, insomnia, mycobacterium, mycosis, nervousness, pseudomonas, rheumatism, staphylococcus and yeast.

However, as many as fifteen years ago, investigators found that grapefruit juice can markedly augment oral drug bioavailability. This was an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used as a flavour supplement to mask the taste of the ethanol 5. Studies that followed, confirmed that grapefruit juice significantly increased the oral bioavailability of felodipine 67. Subsequent studies probed the constituents of grapefruit juice, its interaction with various other drugs and the mechanisms of action of those interactions. Several grapefruit juice-drug interactions were discovered and these remain a potential concern especially since the juice and drugs are often consumed together at breakfast. An increasing number of adverse drug reactions might be avoided on the basis of knowledge about the interaction of grapefruit juice and relevant drugs. Therefore, patients need to be educated about the hazards (and advantages) of grapefruit interaction with medication. In recent years, more drugs have been investigated for their interaction with grapefruit juice and new models have been proposed for the mechanism of such interaction. This article presents a simplistic summary of most examples of such interactions and also explores the phytochemistry and possible mechanisms of action involved in drug-grapefruit juice interactions in light of recent studies on this subject.

Mechanism of action

The mechanism of action of this interaction involves inhibition of the CYP 3A4, a member of the cytochrome P 450 (CYP) enzyme system. CYP is a large multigene family of heme-containing enzymes located in the endoplasmic reticulum of cells throughout the body. It is especially concentrated in the liver and intestinal wall where it is involved in oxidative biotransformation of various endogenous and exogenous substances. CYP 3A isoforms constitute 70% of CYP enzymes in enterocytes 89. P-glycoprotein (Pgp), a member of the ABC (adenosine triphosphate-binding cassette), is another membrane transporter located in the apical brush border of enterocytes. Once taken up by the enterocytes, a lipophilic drug may be metabolized by CYP 3A4 or be pumped back into the lumen by the Pgp. Hence the oral delivery of many drugs is limited by the actions of CYP 3 A4 or Pgp. Metabolism by the CYP 3A4 will also occur in the liver before the drug finally enters the systemic circulation. Grapefruit juice causes inhibition of CYP 3A4 and thus serves to increase the bioavalability of the drug by decreasing its pre-systemic metabolism 10. This action is in essence, similar to that caused by CYP-inhibiting drugs like itraconazole, ketoconazole and erythromycin 111213.

Grapefruit juice causes quick and irreversible sustained inhibition of the CYP system, possibly by greatly accelerating the degradation of these enzymes while also reducing translation from its mRNA. However, the process of transcription of mRNA from the cell DNA is not affected. Overall, grapefruit juice reduces the levels of CYP 3A4 in the cells by as much as 47% within four hours of ingestion of grapefruit juice with the resultant increased bioavailability being maintained for as long as 24 hours, by which time 30% of its effect is still detectable 14151617. It has been observed that decreased content of CYP3A4 was not associated with increased CYP3A4 mRNA, probably indicating the absence of a feedback mechanism for CYP3A4 expression. Restoration of CYP3A4 activity would therefore require denovo synthesis or enterocyte replacement, accounting for the prolonged duration of the actions of grapefruit juice 18.

Grapefruit juice shows a high variability of the magnitude of effect among individuals. This variability is dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 have the highest proportional increase 1920. However, the effects of grapefruit juice are predominantly on the intestinal CYP rather than hepatic CYP. This is shown by the fact that most of the drugs that are involved in interaction with grapefruit juice undergo their primary metabolism at the intestinal level and in usual quantity, grapefruit juice does not affect the pharmacokinetics of these drugs when they are administered intravenously. Furthermore, while it increases the area under the plasma concentration-time curve (AUC), it has no significant effect on the half life of the drugs 10212223.

In contrast to the clear inhibitory effects of grapefruit juice on CYP 3A4, the effects of grapefruit juice on Pgp are controversial, ranging from activation to inhibition. Earlier results have shown grapefruit juice to cause activation of Pgp in vitro 24. Any such activation in vivo will mean a greater efflux of the drug back into the lumen, thereby decreasing the oral bioavailability of that drug and at least partially, if not completely offsetting the effects produced by the inhibition of CYP system of enzymes. This is taken as an explanation for the less-than-expected increase in the bioavailability of drugs that are established substrates of Pgp 24. However, grapefruit juice does not change the absorption of digoxin, a prototypical P-glycoprotein substrate, likely because it has high inherent oral bioavailability 1725. However, recent studies have demonstrated the inhibition of Pgp by grapefruit juice both by its down-regulation and inhibition of function 2627. For example, grapefruit juice increases the bioavailability of cyclosporine. This effect is thought to be primarily though Pgp inhibition (instead of CYP3A4 inhibition) since orange juice mediated reduction in enterocyte CYP3A4 concentrations did not produce a similar increase in bioavailability 17. In fact, grapefruit juice has also shown inhibition of multidrug resistant protein 2 (MRP2), an efflux protein closely related to Pgp in terms of its expression and function 26.

Yet, in spite of all what is known, the mechanism of action of grapefruit juice-drug interaction requires further investigation. Investigators still need to determine for certainty any in vivo effect of grapefruit juice on Pgp. One study 28 has also reported the action of grapefruit juice independent of its actions on Pgp and CYP 3A4. This also requires further investigation. Similarly, grapefruit and even orange juice have also recently been shown to be potent in vitro inhibitors of a number of organic anion-transporting polypeptides (OATPs) that are involved in apical-to-basal transport of drugs in the small intestine 17182529. They were also found to decrease the absorption of the non-metabolized OATP substrate, fexofenadine hence pointing towards inhibition of intestinal uptake transporters by fruit juices to decrease drug bioavailability. This newly proposed mechanism of action and its effect vis a vis various medications also demands further investigation 2529.

Assessment of the in vitro CYP inhibition potential for these natural products has important implications for predicting the likelihood of natural product-drug interactions if these products are taken concomitantly. The susceptibility of CYP3A4 to modulation by food constituents may be related to its high level of expression in the intestine, as well as its broad substrate specificity. Reported ethnic differences in the activity of this enzyme may be partly due to dietary factors. Food-drug interactions involving CYP1A2, CYP2E1, glucuronosyltransferases and glutathione S-transferases have also been documented, although most of these interactions are modest in magnitude and clinically relevant only for drugs that have a narrow therapeutic range. Recently, interactions involving drug transporters, including P-glycoprotein and the organic anion transporting polypeptide, have also been identified. Hence a lot of food varieties have the potential to require dosage adjustment to maintain drug concentrations within their therapeutic windows, especially with drugs that have a high first pass degradation 30. Further research is needed to determine the scope, magnitude and clinical importance of food effects on drug metabolism and transport.

Relevant phytochemistry

Another area in which the search for definite answers continues, is the quest to find the active constituents of grapefruit juice that are responsible for its actions on CYP enzyme systems and Pgp. The components of grapefruit juice that are responsible for clinical drug interactions have yet to be fully determined but the compounds thought to be responsible for this action include flavonoid glycosides (narirutin, naringin, naringinen, quercetin, kaemferol, hesperidin, neohesperidin, didymin, and poncirin) 831323334, furanocoumarins (6',7'-dihydroxybergamottin, bergamottin) and sesquiterpen (nootkatone)822323536.

Flavanoids exist in grapefruit juice in the form of glycosides, with naringin being the most abundant. Upon ingestion, these are converted to aglycones and sugars by the action of intestinal flora. Being polyphenolic and electron rich, these compounds can theoretically inhibit the CYP enzymes. However, studies have at most shown an in vitro effect by these compounds on the these enzymes and have failed to identify any in vivo effect by them 3738, leading to an implication that they are probably not the main active ingredients of grapefruit juice 139. Studies have even failed to demonstrate any sort of activity in naringin although its metabolite naringinin was observed to be active in vitro. Yet, because of their huge quantities in grapefruit juice, and the fact that naringin is not present in other citrus juices, flavanoids remain a subject of research.

The main focus at present, however, is on furanocoumarins. This group includes Bergamottin, its derivative 6' 7' dihydroxybergamottin (DHB) and a host of other compounds 40. Controversy still exists on the degree of their role in the inhibitory effects of grapefruit juice. Several studies have shown DHB 233540 and to an extent Bergamottin 23 to be important contributors to the grapefruit juice effect. In one study, the inhibitory potency of DHB and four recently isolated furanocoumarins, when mixed with one another, almost approached that of grapefruit juice. Omission of any of the components resulted in decreased potency, suggesting that all major furanocoumarins contribute to the inhibitory effects of grapefruit juice 40. However, others have suggested that DHB and Bergamottin are not the primary substances responsible for inhibition of CYP activity clinically 4142. For now, this topic also remains a subject of intense research.

Drug-grapefruit juice interactions

Anti-hypertensive drugs and amiodarone

1,4-Dihydropyridine calcium antagonists are lipid soluble drugs used in the treatment of essential hypertension and angina pectoris and metabolized in vivo by CYP3A4. Since the effects of grapefruit juice were first noticed with felodipine, this class of drugs has been intensively studied with grapefruit juice. The degree to which the intestinal CYP system metabolizes this class of drugs and affects their oral bioavailability varies markedly. In a study done by Lundahl J et al., it was found that the intake of grapefruit juice led to an increase in the oral bioavailability by 112% 43. However, this study also found out that the intravenous pharmacokinetics of felodipine were not significantly altered with grapefruit juice. The main acute effect of the grapefruit juice on the plasma concentrations of felodipine was believed to be mediated by inhibition of gut wall metabolism. Grapefruit juice-felodipine interaction increases with increasing frequency and amount of grapefruit juice ingestion, hence it has been determined that an interval of 2–3 days between grapefruit juice intake and felodipine administration is necessary if the interaction is to be avoided 44. Blood pressure responses to felodipine with grapefruit juice have also been assessed in the elderly and the systolic and diastolic blood pressures were found to be lower with grapefruit juice in the single-dose state, whereas they were not different between treatments in the steady-state dose 45. The different blood pressure results between the studies can be explained by felodipine concentration-blood pressure response relationships. The elderly should be particularly cautioned about concomitant grapefruit juice and felodipine ingestion.

In the benzothiazepine calcium channel antagonists group, diltiazem has been found to have an increased bioavailability on co administration of a single intake of grapefruit juice. Inhibition of intestinal metabolism and/or P-glycoprotein efflux transport was believed to be possibly responsible for this effect 46. However in contrast to this, another study showed the bioavailability to be unchanged with grapefruit juice suggesting that factors other than biotransformation may be contributing 47.

Compared with water, grapefruit juice increased the maximum concentration of nisoldipine and reduced the time to reach maximum nisoldipine concentration 48. However, the effects of grapefruit pulp intake were smaller than those produced by grapefruit juice intake, indicating that grapefruit pulp and juice have different effects on the pharmacokinetics 49.

A clinical study was performed to see the duration of this interaction in the body. Eight healthy volunteers were given grapefruit juice at 14, 38, 72 and 96 hours. Compared with the control group, the maximum plasma concentration of nisoldipine was significantly increased after grapefruit juice intake in at 0 and 14 hours, and the plasma concentration was significantly increased at each time till 72 hours 50. It is therefore necessary to withhold grapefruit juice for at least 3 days before administration of the drug to prevent grapefruit juice -nisoldipine interaction.

Regarding verapamil, there are conflicting reports about its interaction with grapefruit juice. One study showed an increase in its bioavailability at steady state 51 while another showed no significant change in pharmacokinetics on a single administration.

ACE-inhibitors like enalapril, captopril, lisinopril and ramipril have not shown any interaction with grapefruit juice although such an interaction might be possible with angiotensin II type 1 receptor antagonists like losartan and valsartan 18. Thiazide diuretics and alph 1 adrenergic antagonists (doxazosin, terazosin, prazosin) have also shown no interaction with grapefruit juice 18.

Amiodarone, an antiarrythmic, is metabolized by CYP3A to N-desethylamiodarone (N-DEA), a metabolite more potent than the parent drug 17. On interaction with grapefruit juice, there has been shown to be complete inhibition of N-DEA production 52 leading to an overall decrease in the arrythmogenic side effects of amiodarone 17. These results are in agreement with in vitro data pointing to the involvement of CYP3A in the metabolism of amiodarone and other Ca antagonists, suggesting that this interaction should be taken into account when prescribing this antiarrhythmic drug. Similarly grapefruit juice has been found to increase oral nimodipine bioavailability 53. The same cannot be said of amlodipine, on which grapefruit juice has no appreciable effect 54.

One of the possible active ingredients in commercial grapefruit juice is Bergamottin, as mentioned before. This was determined after studying the effects of the furanocoumarin derivative on nifedipine (NFP) pharmacokinetics, suggesting that bergamottin in grapefruit might be the substance that elevates the NFP plasma concentrations 55.

Further studies have also been done to determine if even unprocessed grapefruit could cause drug interactions. It has been shown that unprocessed grapefruit can cause a drug interaction with felodipine 56. 6', 7'-Dihydroxybergamottin and naringin were implicated to be more important in this case because they are present in higher concentrations in grapefruit extracts.

Antimicrobials

With antivirals, authors concluded that concomitant administration of grapefruit juice increases gastric pH and delays indinavir absorption but does not uniformly affect the systemic bioavailability of indinavir in HIV-infected subjects 5758. Similarly grapefruit juice has been shown clinically to not significantly affect amprenavir pharmacokinetics 59. It is suggested that this may be because the primary metabolism of these drugs is not in the small intestine.

On the other hand regarding saquinavir, it has been shown that grapefruit juice increases the bioavailability of saquinavir without affecting its clearance, suggesting that inhibition of intestinal CYP3A4 may contribute 60. And since the antiretroviral effect of saquinavir is dose-dependent, it has been suggested that inhibition of CYP3A4 may represent a way to enhance its effectiveness without increasing the dose.

Amongst anti malarials, grapefruit juice significantly increases the oral bioavailability of artemether but does not prevent the time-dependent reduction in bioavailability or elimination half-life, suggesting a role for intestinal CYP3A4 in the presystemic metabolism of artemether 6162. Similar results have also been seen after a single oral dose of praziquantel with 250 ml of grapefruit juice 63.

Quinine appears to be unaffected in its pharmacokinetics. Since quinine is a low clearance drug with a relatively high oral bioavailability, and is primarily metabolised by human liver CYP3A4, the lack of effect of grapefruit juice on quinine pharmacokinetics again supports the view that the site of CYP inhibition by grapefruit juice is mainly in the gut 1764. However for quinidine, grapefruit juice reduces its total clearance and increases the elimination half-life by 19% 65.

In antibiotics, administration of grapefruit juice increased the time to peak concentration of clarithromycin but did not affect other pharmacokinetic parameters 66 while in antiparasitics, albendazole showed an increase in bioavailability upon administration of grapefruit juice 67.

Benzodiazepines and CNS drugs

A marked interaction between oral midazolam and grapefruit juice has been found and the data is consistent again with a reduced first-pass metabolism of midazolam, resulting in increased bioavailability of midazolam 6869. The clinical importance of this is especially for patients with other causes for increased midazolam bioavailability such as advanced age, cirrhosis of the liver, and administration of other inhibitors of cytochrome P450. Thus, patients with liver cirrhosis are more dependent on the intestine for metabolism of CYP3A4 substrates than subjects with normal liver function. Another important implication of this interaction is in dentistry. Oral midazolam is a frequently used sedative in pediatric dentistry. Although an oral form of midazolam is now commercially available, some practitioners continue to use the IV midazolam as an oral medication. If the injectible form of midazolam is administered orally, its bitter taste requires the use of a flavoring agent like grapefruit juice. This results in increased blood plasma levels of midazolam causing excessive levels of sedation for the pediatric patient. Grapefruit juice therefore should be contraindicated for use with oral midazolam especially in such patients 70. Similar results have also been seen with triazolam 71.

One study however, did show that grapefruit juice did not have any particular interaction with oral doses of 10 mg midazolam and 0.25 mg triazolam in healthy young subjects 72. However, since more studies have determined increases in midazolam and triazolam bioavailbility, grapefruit juice should be administered with caution with these drugs. However, alprazolam remains unaffected in pharmacokinetics or pharmacodynamics due to its high bioavailability 73.

Among antipsychotics, clozapine remained unaffected after consumption of regular-strength grapefruit juice, usually taken as 250 mL b.i.d., for 14 days 74. One reason for this is that enzymes other than CYP3A4 also mediate clozapine disposition. Haloperidol remains unaffected by grapefruit juice 75.

In anti convulsants, grapefruit juice increases the bioavailability of carbamazepine 76 but does not affect the pharmacokinetics of phenytoin 77.

Grapefruit juice considerably increases plasma buspirone concentrations 78 and also increases sertraline bioavailability 79. Grapefruit juice therefore should be contraindicated during administration of buspirone and sertraline.

Antihistamines and Serotonin Analogs

A number of studies have shown that a single glass of grapefruit juice produced an individual-dependent, variable increase in the systemic bioavailability of cisapride by inhibition of intestinal cytochrome P450 3A4 (CYP3A4) activity. 808182 It has therefore been recommended that concomitant use of high amounts of grapefruit juice with cisapride should be avoided, at least in patients with risk factors for cardiac arrhythmia.

The effect of grapefruit juice on racemic nitrendipine was also to increase its bioavailability and it was found that it inhibits the stereoselective metabolism of nitrendipine in humans 83.

Regarding terfenidine, the ingestion of grapefruit juice leads to its enhanced systemic bioavailability 8485. This is especially important because the raised levels of terfenidine can prolong the QT interval in the electrocardiogram sufficiently to precipitate the ventricular arrhythmia of Torsade-des-pointes 86. Incidentally, both terfenidine and cisapride have been globally withdrawn from the market due to serious cardiac arrythmias precipitated by their interaction with other drugs if simultaneously taken.

Statins and other cholesterol-lowering agents

Taking simvastatin first, the active ingredient bergamottin has been shown to inhibit simvastatin (SV) metabolism and increase the serum concentrations of simvastatin and its active metabolite simvastatin acid, and, to a lesser extent, those of active and total HMG-CoA reductase inhibitors 8788. The probable mechanism of this interaction was also the inhibition of CYP3A4-mediated first-pass metabolism of simvastatin by grapefruit juice in the small intestine. Bergamottin (BG) and naringenin (NRG) could therefore be applied as markers in food-drug interaction studies in order to adjust posology and the dose of simvastatin should be accordingly reduced.

Another study further found out that, when simvastatin is taken 24 hours after ingestion of "high-dose" grapefruit juice, the effect on the concentration of simvastatin is only about 10% of the effect observed during concomitant intake of grapefruit juice and simvastatin. It was also shown that the interaction potential of even high amounts of grapefruit juice with CYP3A4 substrates dissipates within 3 to 7 days after ingestion of the last dose of grapefruit juice 89.

The grapefruit juice effect has also been studied on lovastatin. Lovastatin and its active metabolite, lovastatin acid had greatly increased serum concentrations after grapefruit juice administration 90. However, one other study has shown a minimal effect of a glass of regular-strength grapefruit juice on plasma concentration after a 40 mg evening dose of lovastatin 91.

Although grapefruit juice also increases the AUC of atorvastatin, the actual increase in activity is fairly modest, possibly due to a simultaneous effect of decreasing the AUC of active metabolites of atorvastatin 17. Regardless, grapefruit juice should not be concomitantly ingested with atorvastatin, lovastatin or simvastatin. On the other hand, pravastatin, fluvastatin and rosuvastatin are three statin drugs that have been shown not to interact with grapefruit juice 18. These may be useful alternatives in settings where there is a concern regarding potential interaction with grapefruit juice.

Other cholesterol-lowering agents like nicotinic acid and common fibric acid derivatives and bile acid sequestrants have shown no interaction, and therefore may be safely used, with grapefruit juice 18.

Chemotherapeutics

In patients with autoimmune diseases, the effect of chronic grapefruit juice administration on steady state blood concentrations of cyclosporine and metabolites is an increase in both parent and metabolite profiles 92. This interaction was studied in renal transplant recipients. Administration of cyclosporine with grapefruit juice compared with water induced a moderate, butsignificant increase in the systemic exposure of cyclosporine 9394. Most of these studies involving cyclosporine were done on adult patients. However, one study was also done in the paediatric population. This study showed that alterations in cyclosporine absorption and elimination only occur with concurrent grapefruit juice ingestion when stable pediatric renal transplant patients are taking the oral cyclosporine solution, but not the microemulsion formulation 95.

Regarding prednisolone and etoposide, grapefruit juice has been found to have no significant effect on the metabolism of prednisolone 96 but in the case of etoposide, it has been shown to decrease its bioavailability 97.

Conclusion

In light of the wide ranging effects of grapefruit juice on the pharmacokinetics of various drugs, physicians need to be aware of these interactions and should make an attempt to warn and educate their patients regarding potential consequences of concomitant ingestion of these two items. Patient-to-patient variability should be kept in mind and elderly should be particularly warned about these interactions since they are more prone to grapefruit juice-drug interactions 17. Physicians should also consider using these effects to their own advantage in order to reduce the dosage requirements of certain drugs. However, since further research is required into the mechanism of action of grapefruit juice, it is still premature to recommend it as an adjunctive booster with other drugs.

Abbreviations

AUC = area under the plasma concentration-time curve

CYP = cytochrome P -450

DEA = desethylamiodarone

DHB = dihydroxybergamottin

HMG – CoA = 3 – hydroxyl – 3 – methylglutaryl coenzyme A

NFP = nifedipine

OATP = organic anion-transporting polypeptides

Pgp = P – glycoprotein

RDA = Recommended daily allowance

SV = simvastatin

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

Both authors contributed equally.

Acknowledgements

This was an independent review done by the authors.

http://www.cdc.gov/nccdphp/dnpa/5ADay/month/index.htm Inhibition of atherosclerosis by dietary pectin in microswine with sustained hypercholesterolemia Cerda JJ Normann SJ Sullivan MP Circulation 1994 89 1247 1253 8124813 Inhibition of human cancer cell proliferation and delay of mammary cell tumorigenesis by flavonoids and citrus juices So FV Guthrie N Chambers AF Moussa M Carol KK Nutr Cancer 1996 26 167 181 8875554 Inhibition of mammary cancer by citrus flavanoids Guthrie N Carol KK Adv Exp Med Biol 1998 439 227 236 9781306 Ethanol enhances the hemodynamic effects of felodipine Bailey DG Spence JD Edgar B Bailiff CD Arnold JM Clin Invest Med 1989 12 357 362 2612087 Interaction of citrus juices with felodipine and nifedipine Bailey DG Spence JD Munoz C Arnold JM Lancet 1991 337 268 269 10.1016/0140-6736(91)90872-M 1671113 Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine- and its potential clinical relevance Edgar B Bailey D Bergstrand R Johnsson G Regardh CG Eur J Clin Pharmacol 1992 42 313 317 10.1007/BF00266354 1577050 Drug-grapefruit juice interactions Kane GC Lipsky JJ Mayo Clin Proc 2000 75 933 942 10994829 Characterization of human small intestinal cytochromes P 450 Zhang QY Dunbar D Ostrowska A Zeisloft S Yang J Kaminsky LS Drug Metab Dispos 1999 27 804 809 10383924 Effects of grapefruit juice ingestion-pharmacokinetics and hemodynamics of intravenously and orally administered felodipine in healthy men Lundahl J Regardh CG Edgar B Johnsson G Eur J Clin Pharmacol 1997 25 139 145 10.1007/s002280050263 Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole Kivisto KT Lamberg TS Kantola T Neuvonen PJ Clin Pharmacol Ther 1997 62 348 354 10.1016/S0009-9236(97)90038-2 9333111 Different effects of itraconazole on fluvastatin and lovastatin Kivisto KT Kantola T Neuvonen PJ Br J Clin Pharmacol 1998 46 49 53 10.1046/j.1365-2125.1998.00034.x 9690949 Tacrolimus oral bioavailability doubles with coadministration of ketoconazole Floren LC Bekersky I Benet LZ Clin Pharmacol Ther 1997 62 41 49 10.1016/S0009-9236(97)90150-8 9246018 Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felopdipine in healthy subjects Lundahl J Regardh CG Edgar B Johnsson G Eur J Clin Pharmacol 1995 49 61 67 10.1007/BF00192360 8751023 Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit juice constituents: decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins Schmiedlien-Ren P Edwards DJ Fitzsimmons ME Drug Metab Dispos 1997 25 1228 1233 9351897 Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP 3A protein expression Lown KS Bailey DG Fontana RJ J Clin Invest 1997 99 2545 2553 508096 9153299 Undesirable effects of citrus juice on the pharmacokinetics of drugs: focus on recent studies Saito M Hirata-Koizumi M Matsumoto M Urano T Hasegawa R Drug Saf 2005 28 677 94 10.2165/00002018-200528080-00003 16048354 Interaction between grapefruit juice and cardiovascular drugs Bailey DG Dresser GK Am J Cadriovasc Drugs 2004 4 281 297 10.2165/00129784-200404050-00002 Food-drug interaction: grapefruit juice augments drug bioavailability mechanism, extent and relevance Dahan A Altman H Eur J Clin Nutr 2004 58 1 9 10.1038/sj.ejcn.1601736 14679360 Grapefruit juice-drug interactions Bailey DG Malcolm J Arnold O Spence JD Br J Clin Pharmacol 2004 46 101 10 10.1046/j.1365-2125.1998.00764.x Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man Kupferschmidt HH Fattinger KE Ha HR Follath F Krahenbuhl S Br J Clin Pharmacol 1998 45 355 359 10.1046/j.1365-2125.1998.t01-1-00687.x 9578182 Interaction between grapefruit juice and midazolam in humans Kupferschmidt HH Ha HR Ziegler WH Meier PJ Krahenbuhl S Clin Pharmacol Ther 1995 58 20 28 10.1016/0009-9236(95)90068-3 7628179 Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice Greenblatt DJ von Moltke LL Harmatz JS Chen G Weemhoff JL Jen C Kelley CJ LeDuc BW Zinny MA Clin Pharmacol Ther 2003 74 121 9 10.1016/S0009-9236(03)00118-8 12891222 Grapefruit juice activates P-glycoprotein-mediated drug transport Soldner A Christians U Susuanto M Wacher VJ Silverman JA Benet LZ Pharm Res 1999 16 478 485 10.1023/A:1011902625609 10227700 The effects of fruit juices on drug disposition: a new model for drug interactions Dresser GK Bailey DG Eur J Clin Invest 2003 33 Suppl 2 10 6 10.1046/j.1365-2362.33.s2.2.x 14641551 Effects of grapefruit juice and orange juice components on P-glycoprotein- and MRP2-mediated drug efflux Honda Y Ushigome F Koyabu N Morimoto N Shoyama Y Uchiumi T Kuwano M Ohtani H Sawada Y Br J Pharmacol 2004 143 856 864 10.1038/sj.bjp.0706008 15504753 Effects of grapefruit juice on the multidrug transporter P-glycoprotein in the human proximal tubular cell line HK-2 Romiti N Tramonti G Donati A Chieli E Life Sci 2004 76 293 302 10.1016/j.lfs.2004.06.015 15531381 6'7' dihydroxybergamottin in grapefruit juice and sivelle orange juice: effects on cyclsporin disposition, enetrocyte CYP 3A4 and P-glycoprotein Edwards DJ Fitzsimmons ME Schuetz EG Clin Pharmacol Ther 1999 65 237 244 10.1016/S0009-9236(99)70102-5 10096255 Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine Dresser GK Bailey DG Leake BF Schwarz UI Dawson PA Freeman DJ Kim RB Clin Pharmacol Ther 2002 71 11 20 10.1067/mcp.2002.121152 11823753 Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance Fuhr U Drug Saf 1998 18 251 72 10.2165/00002018-199818040-00002 9565737 Variance of common flavonoids by brand of grapefruit juice Ross SA Ziska DS Zhao K ElSohly MA Fitoterapia 2000 71 154 61 10.1016/S0367-326X(99)00131-8 10727812 Grapefruit juice and drugs: a hazardous combination? Lohezic-Le Devehat F Marigny K Doucet M Javaudin L Therapie 2000 57 432 45 Inhibition of dihydropyridine metabolism in rat and human liver microsomes by flavanoids found in grapefruit juice Miniscalco A Lundahl J Regardh CG Edgar B Eriksson UG J Pharmacol Exp Ther 1992 261 1195 1199 1602384 In vitro inhibition of midazolam and quinidine metabolism by flavanoids Ha Hr Chen J Leuenberger PM Freiburghaus AU Follath F Eur J Clin Pharmacol 1995 48 367 371 8641324 6'7'-Dihydroxybergamottin contributes to the grapefruit juice effect Kakar SM Paine MF Stewart PW Watkins PB Clin Pharmacol Ther 2004 75 569 79 10.1016/j.clpt.2004.02.007 15179411 Specific CYP 3 A4 inhibitors in grapefruit juice: furocoumarin dimmers as components of drug interaction Fukuda K Ohta T Oshima Y Ohashi N Yoshikawa M Yamazoe Y Pharmacogenetics 1997 7 391 396 10.1097/00008571-199710000-00008 9352575 Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics Bailey DG Arnold JM Strong HA Munoz C Spence JD Clin Pharmacol ther 1993 54 589 594 8275614 Grapefruit juice-felodipine interaction: mechanism, predictability and effect of naringin Bailey DG Arnold JM Munoz C Spence JD Clin Pharmacol Ther 1993 53 637 642 8513655 Naringin and naringenin are not primary CYP 3A inhibitors in grapefruit juice Edwards DJ Bernier SM Life Sci 1996 59 1025 1030 10.1016/0024-3205(96)00417-1 8809221 Role of furanocoumarin derivatives on grapefruit juice-mediated inhibition of human CYP3A activity Guo LQ Fukuda K Ohta T Yamazoe Y Drug Metab Dispos 2000 28 766 71 10859150 Grapefruit Juice-felodipine interaction: effect of naringin and 6, 7-dihydroxybergamottin in humans Bailey DG Kreeft JH Munoz C Freeman DJ Bend JR Clin Pharmacol Ther 1998 64 248 256 10.1016/S0009-9236(98)90173-4 9757148 Bergamottin, lime juice, and red wine as inhibitors of cytochrome P450 3A4 activity: comparison with grapefruit juice Bailey DG Dresser GK Bend JR Clin Pharmacol Ther 2003 73 529 37 10.1016/S0009-9236(03)00051-1 12811362 Effects of grapefruit juice ingestion – pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men Lundahl J Regardh CG Edgar B Johnsson G Eur J Clin Pharmacol 1997 52 139 45 10.1007/s002280050263 9174684 Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model Takanaga H Ohnishi A Matsuo H Murakami H Sata H Kuroda K Urae A Higuchi S Sawada Y Br J Clin Pharmacol 2000 49 49 58 10.1046/j.1365-2125.2000.00140.x 10606837 Grapefruit juice – felodipine interaction in the elderly Dresser GK Bailey DG Carruthers SG Clin Pharmacol Ther 2000 68 28 34 10.1067/mcp.2000.107524 10945313 Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers Christensen H Asberg A Holmboe AB Berg KJ Eur J Clin Pharmacol 2002 58 515 20 10.1007/s00228-002-0516-8 12451428 Lack of effect of grapefruit juice on diltiazem bioavailability in normal subjects Sigusch H Henschel L Kraul H Merkel U Hoffmann A Pharmazie 1994 49 675 9 7972311 Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics Bailey DG Arnold JM Strong HA Munoz C Spence JD Clin Pharmacol Ther 1993 54 589 94 8275614 [Effect of grapefruit pulp on the pharmacokinetics of the dihydropyridine calcium antagonists nifedipine and nisoldipine] Ohtani M Kawabata S Kariya S Uchino K Itou K Kotaki H Kasuyama K Morikawa A Seo I Nishida N Yakugaku Zasshi 2002 122 323 9 10.1248/yakushi.122.323 12040751 Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects Takanaga H Ohnishi A Murakami H Matsuo H Higuchi S Urae A Irie S Furuie H Matsukuma K Kimura M Kawano K Orii Y Tanaka T Sawada Y Clin Pharmacol Ther 2000 67 201 14 10.1067/mcp.2000.104215 10741622 Effects of grapefruit juice and smoking on verapamil concentrations in steady state Fuhr U Muller-Peltzer H Kern R Lopez-Rojas P Junemann M Harder S Staib AH Eur J Clin Pharmacol 2002 58 45 53 10.1007/s00228-002-0436-7 11956673 Dramatic inhibition of amiodarone metabolism induced by grapefruit juice Libersa CC Brique SA Motte KB Caron JF Guedon-Moreau LM Humbert L Vincent A Devos P Lhermitte MA Br J Clin Pharmacol 2000 49 373 8 10.1046/j.1365-2125.2000.00163.x 10759694 Grapefruit juice increases oral nimodipine bioavailability Fuhr U Maier-Bruggemann A Blume H Muck W Unger S Kuhlmann J Huschka C Zaigler M Rietbrock S Staib AH Int J Clin Pharmacol Ther 1998 36 126 32 9562227 Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine Vincent J Harris SI Foulds G Dogolo LC Willavize S Friedman HL Br J Clin Pharmacol 2000 50 455 63 10.1046/j.1365-2125.2000.00283.x 11069440 Effects of furanocoumarin derivatives in grapefruit juice on nifedipine pharmacokinetics in rats Mohri K Uesawa Y Pharm Res 2001 18 177 82 10.1023/A:1011028401189 11405288 Grapefruit-felodipine interaction: effect of unprocessed fruit and probable active ingredients Bailey DG Dresser GK Kreeft JH Munoz C Freeman DJ Bend JR Clin Pharmacol Ther 2000 68 468 77 10.1067/mcp.2000.110774 11103749 Effects of grapefruit juice on pharmacokinetic exposure to indinavir in HIV-positive subjects Shelton MJ Wynn HE Hewitt RG DiFrancesco R J Clin Pharmacol 2001 41 435 42 10.1177/00912700122010140 11304900 Effect of Seville orange juice and grapefruit juice on indinavir pharmacokinetics Penzak SR Acosta EP Turner M Edwards DJ Hon YY Desai HD Jann MW J Clin Pharmacol 2002 42 1165 70 10.1177/009127002401382650 12362932 Single-dose pharmacokinetics of amprenavir coadministered with grapefruit juice Demarles D Gillotin C Bonaventure-Paci S Vincent I Fosse S Taburet AM Antimicrob Agents Chemother 2002 46 1589 90 127190 11959608 10.1128/AAC.46.5.1589-1590.2002 Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man Kupferschmidt HH Fattinger KE Ha HR Follath F Krahenbuhl S Br J Clin Pharmacol 1998 45 355 9 10.1046/j.1365-2125.1998.t01-1-00687.x 9578182 The effect of grapefruit juice on the time-dependent decline of artemether plasma levels in healthy subjects Van Agtmael MA Gupta V van der Graaf CA van Boxtel CJ Clin Pharmacol Ther 1999 66 408 14 10.1053/cp.1999.v66.a101946 10546925 Grapefruit juice increases the bioavailability of artemether Van Agtmael MA Gupta V van der Wosten TH Rutten JP van Boxtel CJ Eur J Clin Pharmacol 1999 55 405 10 10.1007/s002280050648 10456492 Interaction between grapefruit juice and praziquantel in humans Castro N Jung H Medina R Gonzalez-Esquivel D Lopez M Sotelo J Antimicrob Agents Chemother 2002 46 1614 6 127135 11959616 10.1128/AAC.46.5.1614-1616.2002 Grapefruit juice has no effect on quinine pharmacokinetics Ho PC Chalcroft SC Coville PF Wanwimolruk S Eur J Clin Pharmacol 1999 55 393 8 10.1007/s002280050646 10456490 Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine Damkier P Hansen LL Brosen K Br J Clin Pharmacol 1999 48 829 38 10.1046/j.1365-2125.1999.00099.x 10594487 Effect of grapefruit juice on clarithromycin pharmacokinetics Cheng KL Nafziger AN Peloquin CA Amsden GW Antimicrob Agents Chemother 1998 42 927 9 105569 9559810 Effect of grapefruit juice or cimetidine coadministration on albendazole bioavailability Nagy J Schipper HG Koopmans RP Butter JJ Van Boxtel CJ Kager PA Am J Trop Med Hyg 2002 66 260 3 12139218 Intestinal first pass metabolism of midazolam in liver cirrhosis – effect of grapefruit juice Andersen V Pedersen N Larsen NE Sonne J Larsen S Br J Clin Pharmacol 2002 54 120 4 10.1046/j.1365-2125.2002.01615.x 12207630 Interaction between grapefruit juice and midazolam in humans Kupferschmidt HH Ha HR Ziegler WH Meier PJ Krahenbuhl S Clin Pharmacol Ther 1995 58 20 8 10.1016/0009-9236(95)90068-3 7628179 Oral midazolam-grapefruit juice drug interaction Goho C Pediatr Dent 2001 23 365 6 11572503 Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice Hukkinen SK Varhe A Olkkola KT Neuvonen PJ Clin Pharmacol Ther 1995 58 127 31 10.1016/0009-9236(95)90188-4 7648762 Grapefruit juice does not enhance the effects of midazolam and triazolam in man Vanakoski J Mattila MJ Seppala T Eur J Clin Pharmacol 1996 50 501 8 10.1007/s002280050148 8858279 Effects of repeated ingestion of grapefruit juice on the single and multiple oral-dose pharmacokinetics and pharmacodynamics of alprazolam Yasui N Kondo T Furukori H Kaneko S Ohkubo T Uno T Osanai T Sugawara K Otani K Psychopharmacology (Berl) 2000 150 185 90 10.1007/s002130000438 10907671 Repeated ingestion of grapefruit juice does not alter clozapine's steady-state plasma levels, effectiveness, and tolerability Lane HY Jann MW Chang YC Chiu CC Huang MC Lee SH Chang WH J Clin Psychiatry 2001 62 812 7 11816871 Lack of significant pharmacokinetic interaction between haloperidol and grapefruit juice Yasui N Kondo T Suzuki A Otani K Mihara K Furukori H Kaneko S Inoue Y Int Clin Psychopharmacol 1999 14 113 8 10.1097/00004850-199903000-00008 10220126 Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy Garg SK Kumar N Bhargava VK Prabhakar SK Clin Pharmacol Ther 1998 64 286 8 10.1016/S0009-9236(98)90177-1 9757152 Lack of pharmacokinetic interaction between grapefruit juice and phenytoin in healthy male volunteers and epileptic patients Kumar N Garg SK Prabhakar S Methods Find Exp Clin Pharmacol 1999 21 629 32 10669910 Grapefruit juice substantially increases plasma concentrations of buspirone Lilja JJ Kivisto KT Backman JT Lamberg TS Neuvonen PJ Clin Pharmacol Ther 1998 64 655 60 10.1016/S0009-9236(98)90056-X 9871430 The effects of grapefruit juice on sertraline metabolism: an in vitro and in vivo study Lee AJ Chan WK Harralson AF Buffum J Bui BC Clin Ther 1999 21 11 1890 9 10.1016/S0149-2918(00)86737-5 10890261 Stereoselective pharmacokinetics of cisapride in healthy volunteers and the effect of repeated administration of grapefruit juice Desta Z Kivisto KT Lilja JJ Backman JT Soukhova N Neuvonen PJ Flockhart DA Br J Clin Pharmacol 2001 52 399 407 10.1046/j.0306-5251.2001.01473.x 11678783 Red wine-cisapride interaction: comparison with grapefruit juice Offman EM Freeman DJ Dresser GK Munoz C Bend JR Bailey DG Clin Pharmacol Ther 2001 70 17 23 10.1067/mcp.2001.116892 11452240 Repeated consumption of grapefruit juice considerably increases plasma concentrations of cisapride Kivisto KT Lilja JJ Backman JT Neuvonen PJ Clin Pharmacol Ther 1999 66 448 53 10.1016/S0009-9236(99)70007-X 10579471 Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans Soons PA Vogels BA Roosemalen MC Schoemaker HC Uchida E Edgar B Lundahl J Cohen AF Breimer DD Clin Pharmacol Ther 1991 50 394 403 1914375 Excessive terfenadine level due to drinking grapefruit juice Van den Anker JN de Wildt SN Ned Tijdschr Geneeskd 1997 141 1976 8 9550749 Grapefruit juice-terfenadine single-dose interaction: magnitude, mechanism, and relevance Rau SE Bend JR Arnold MO Tran LT Spence JD Bailey DG Clin Pharmacol Ther 1997 61 401 9 10.1016/S0009-9236(97)90190-9 9129557 Grapefruit juice alters the systemic bioavailability and cardiac repolarization of terfenadine in poor metabolizers of terfenadine Honig PK Wortham DC Lazarev A Cantilena LR J Clin Pharmacol 1996 36 345 51 8728348 In vitro inhibition of simvastatin metabolism, a HMG-CoA reductase inhibitor in human and rat liver by bergamottin, a component of grapefruit juice Le Goff-Klein N Koffel JC Jung L Ubeaud G Eur J Pharm Sci 2003 18 31 5 10.1016/S0928-0987(02)00222-1 12554070 Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors Lilja JJ Kivisto KT Neuvonen PJ Clin Pharmacol Ther 1998 64 477 83 10.1016/S0009-9236(98)90130-8 9834039 Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin Lilja JJ Kivisto KT Neuvonen PJ Clin Pharmacol Ther 2000 68 384 90 10.1067/mcp.2000.110216 11061578 Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid Kantola T Kivisto KT Neuvonen PJ Clin Pharmacol Ther 1998 63 397 402 10.1016/S0009-9236(98)90034-0 9585793 Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors Rogers JD Zhao J Liu L Amin RD Gagliano KD Porras AG Blum RA Wilson MF Stepanavage M Vega JM Clin Pharmacol Ther 1999 66 358 66 10.1053/cp.1999.v66.a101208 10546919 Dosing implications of a clinical interaction between grapefruit juice and cyclosporine and metabolite concentrations in patients with autoimmune diseases Ioannides-Demos LL Christophidis N Ryan P Angelis P Liolios L McLean AJ J Rheumatol 1997 24 49 54 9002010 Intake of grapefruit juice alters the metabolic pattern of cyclosporin A in renal transplant recipients Hermann M Asberg A Reubsaet JL Sather S Berg KJ Christensen H Int J Clin Pharmacol Ther 2002 40 451 6 12395977 Interaction between cyclosporine and grapefruit juice requires long-term ingestion in stable renal transplant recipients Brunner LJ Munar MY Vallian J Wolfson M Stennett DJ Meyer MM Bennett WM Pharmacotherapy 1998 18 23 9 9469677 Effect of grapefruit juice on cyclosporin A pharmacokinetics in pediatric renal transplant patients Brunner LJ Pai KS Munar MY Lande MB Olyaei AJ Mowry JA Pediatr Transplant 2000 4 313 21 10.1034/j.1399-3046.2000.00136.x 11079273 The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients Hollander AA van Rooij J Lentjes GW Arbouw F van Bree JB Schoemaker RC van Es LA van der Woude FJ Cohen AF Clin Pharmacol Ther 1995 57 318 24 10.1016/0009-9236(95)90157-4 7697949 Effect of grapefruit juice intake on etoposide bioavailability Reif S Nicolson MC Bisset D Reid M Kloft C Jaehde U McLeod HL Eur J Clin Pharmacol 2002 58 491 4 10.1007/s00228-002-0495-9 12389073