Drug interactions with grapefruit juice
Concomitant intake with grapefruit juice increases the concentrations of many drugs in humans. The effect seems to be mediated mainly by suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine wall. This results in a diminished first pass metabolism with higher bioavailability and increased maximal plasma concentrations of substrates of this enzyme. The effect was most pronounced in drugs with high first pass degradation.
The components of grapefruit juice which are the most probable causes of the interaction are furanocoumarins derivatives, but the flavonoid naringenin may also contribute. Concomitant grapefruit juice intake does not generally decrease the variability of drug pharmacokinetic parameters. Therefore, it is recommended that patients abstain from drinking grapefruit juice when they are taking a drug that is extensively metabolised, unless a lack of interaction has already been demonstrated for that drug. It is also recommended that drugs possibly interacting with grapefruit juice should be appropriately labelled.
The grapefruit ( Citrus paradisi ) grows in clusters (like grapes) on a tree. Grapefruit were initially discovered growing in the West Indies in the 1800s, and then brought to the <> United States and Asian countries. Grapefruit is believed to have evolved from the pummelo, a citrus fruit from the Rutaceae family (orange family), through mutation or as a hybrid with the common orange. The grapefruit is larger than an orange but smaller than most pummelos and can yield approximately 2/3 cup of juice. There are two major types of grapefruit: white and pink/ ruby red.
The discovery that grapefruit juice can increase the oral availability of some medications was an accidental discovery made when grapefruit juice was used to mask the taste of ethanol in a study involving the calcium channel blocker felodipine. Since then, more different drugs have shown to enhance oral availability when consumed with grapefruit juice. Most of the drugs affected by grapefruit juice have poor and highly variable oral bioavailability. In addition, most of these drugs are chiefly metabolized in the body by CYP3A4, an enzyme present in the liver and intestine.
The major effect of grapefruit juice appears to reduce “first-pass” metabolism by reducing CYP3A4 activity. Because grapefruit juice does not generally affect the systemic clearance of affected drugs, it appears that grapefruit juice selectively reduces intestinal CYP3A4 activity while having little effect on liver CYP3A4. Grapefruit juice has no effect on drug disposition after intravenous administration and does not alter liver CYP3A4 activity. 1
Clinical significance of grapefruit drug interaction
The clinical significance of grapefruit juice–drug interactions has been debated. Reports of cases of drug toxicity associated with grapefruit juice have been very rare. Although reporting is likely incomplete, there are two reasons why the true incidence of clinically significant grapefruit juice–drug interactions is probably low.
Firstly, the drugs affected by grapefruit juice characteristically have highly variable apparent oral clearance, presumably because of well-established inter-patient variability in activity of intestinal CYP3A4. For this reason, affected drugs must generally have a very wide therapeutic index (an exception is cyclosporine, for which blood level monitoring is generally used to guide individualization of dosing).
Secondly, the relative magnitude of response to grapefruit juice for a given patient appears to largely be a function of his or her relative intestinal CYP3A4 activity. After a standard oral dose of a “susceptible” drug, subjects with very low CYP3A4 activity in the intestine will tend to have a relatively high AUC. Grapefruit juice should have a relatively small effect on pharmacokinetics in these individuals because there is little intestinal CYP3A4 activity to inhibit. In contrast, subjects with high intestinal CYP3A4 activity will have a marked increase in AUC when affected drugs are taken with grapefruit juice. However, these individuals will tend to have unusually low AUCs from standard doses of affected drugs before grapefruit juice administration. A situation in which toxicity could occur would be in patients who have been given higher than usual doses of a susceptible drug and then begin drinking grapefruit juice for the first time. This could occur if the physician increases the drug dose to a desired pharmacologic effect. The dose in a patient with very high intestinal CYP3A4 activity might then be titrated to an unusually high daily dose of drug. A sudden fall in intestinal CYP3A4 activity, as would occur after drinking grapefruit juice, could then result in drug toxicity.
An additional situation might be when a patient has severe liver disease such that the intestine is the major site for metabolism of the drug. Such a patient would be expected to have high systemic exposure to the drug at usual doses; loss of intestinal CYP3A4 activity would further increase the exposure. Finally, patients who have a peculiar susceptibility to toxic effects of a susceptible drug will be more likely to have toxicity when they consume the medicine with grapefruit juice, simply because systemic exposure to the drug would increase. In the future it should be possible to use grapefruit-derived furanocoumarins as additives to certain drugs to improve the oral delivery of some drugs by reducing variability. Such formulations would obviously be no longer susceptible to grapefruit juice interactions. It should also be possible to remove furanocoumarins from grapefruit juice to reduce drug interaction potential.
Finally to thoroughly assess the clinical significance of grapefruit-drug interactions, the type and amount of grapefruit juice must also be considered. Consumption of a single glass of regular-strength grapefruit juice is sufficient to inhibit CYP3A4. The magnitude of interaction may vary depending on the extent of intestinal CYP3A4 expression in an individual patient. This variation between individuals may be significant and is difficult to predict. The grapefruit-drug interaction appears to affect patients with high quantities of small bowel CYP3A4 isoenzymes. 1
Active components of grapefruit juice
Originally, naringin was thought to be the main component responsible for grapefruit-drug interactions. However, studies have shown naringin to be a weak inhibitor of CYP3A4. It was also demonstrated that the administration of isolated naringin to humans, in quantities comparable to those found in grapefruit juice, did not cause the same degree of inhibition as grapefruit juice. 2, 3, 4
The assumption is that the active components in grapefruit juice do not reach the liver in sufficient concentrations to affect CYP3A4 activity; although a variety of juice components have been implicated to inhibit these enzymes. 4, 5
In addition to flavonoids, researchers have also focused on furanocoumarins found in grapefruit juice as CYP3A4 inhibitors. The furanocoumarins such as bergamottin was mainly thought to be responsible for the inhibition of intestinal CYP enzymes. 6, 7 Bergamottin is present in grapefruit juice in concentrations ranging from 2 to 30 μmol/L. Relative exposure to bergamottin is not known, and doses administered were typically larger than those encountered by humans after normal consumption of grapefruit juice. Thus the relevance of bergamottin in the clinical interaction of grapefruit juice in humans is currently uncertain. 8 But, the most abundant and probably the most important single furanocoumarin is 6,7- dihydroxybergamottin (DHB). 1,9,10
When bergamottin administered as a pure substance enhanced the oral bioavailability of some drugs. However, the effect was substantially less than that produced by grapefruit juice even at markedly higher doses of bergamottin than normally present in the juice. It appears probable that the interaction also involves other furanocoumarins present in whole grapefruit juice, possibly acting in combination by additive or synergistic mechanisms. Bergamottin has systemic availability and is metabolized to 6’, 7’- dihydroxybergamottin in humans. 10
The more hydrophilic metabolite, 6’, 7’-dihydroxybergamottin, is often present in grapefruit juice in similar concentrations (0.8 to 58 µmol/L), but initial investigations indicated that it is a less potent with respect to in vitro mechanism-based inactivator of CYP3A4 than bergamottin. 8 However, recent reports by different groups indicate that 6’,7’-dihydroxybergamottin is a more potent mechanism-based inactivator or inhibitor of CYP3A4.
The interaction between grapefruit juice serum and felodipine can be attributed largely to DHB. This establishes DHB as an important contributor to the grapefruit juice effect. These novel findings indicate that DHB could account almost entirely for the effect of the aqueous extract of grapefruit juice on the systemic exposure of felodipine, supporting a major role for DHB in the grapefruit juice effect. 10
Orange juice has no CYP3A4-inhibiting effects. When orange juice was spiked with a synthetic DHB, however, no significant difference between the degrees of inhibition produced by either of the 2 citrus fruits was observed. Therefore, the DHB component in grapefruit appears to be another potent inhibitor of CYP3A4 and is most likely primarily responsible for the interaction.
The furanocoumarins are divided into 6 components: 6',7'-dihydroxybergamottin (DHB), GF-I-1, bergamottin (GF-I-2), GF-I-4, GF-I-5 (bergamottin-6',7'-epoxide), and GFI- 6.12 Significant inhibition of CYP3A4 isoenzyme activity is exhibited by DHB, GF-I-1, and GF-I-4 with minimal activity exhibited by bergamottin (a presumed precursor of GF-I-1 and GF-I-4 and a known ingredient of grapefruit essential oil). 11
The CYP3A4 isoenzyme, which is found in the intestine and liver, accounts for about 40% to 60% of all CYP450 isoenzymes (although it is important to note that grapefruit inhibits CYP450 in the gastrointestinal tract, not the liver) and is involved in the majority of significant CYP450-mediated drug interactions. Inhibition of the CYP3A4 isoenzyme, either reversible or irreversible, will result in a reduced metabolism and metabolic clearance of CYP3A4 substrates. 5
Some of the components of grapefruit such as Paradisin C have also shown CYP3A4 isoenzyme inhibitory activity. Paradicin C was isolated from the grapefruit and the activity was reported as against Paradicin A and B. 12 Other reported components are β-citraurin, D-limonene, myrcene, sabinene 13 and limonoids. Grapefruit contains many flavonoid glycosides, naringenin, quercetin, kaempferol, hesperetin and apigenin being the most abundant among their aglycones. 14, 15, 16
Mechanism of action of grapefruit juice components
DHB and other furanocoumarins appear to reduce CYP3A4 activity by three related but distinct mechanisms, as follows:
(1) Competitive or reversible inhibition,
(2) Mechanism-based inactivation (also called irreversible inhibition), and
(3) Actual loss of CYP3A4 enzyme. 1, 9, 17, 18
The first and most common mechanism is known as competitive inhibition and results from the competition between the inhibitor and substrate for the same CYP isoenzyme required for substrate metabolism and elimination. The effects of competitive inhibition can be observed after administration of the first dose of the inhibitor.
The second mechanism is known as mechanism-based inhibition and occurs with grapefruit juice. The most potent grapefruit components causing a mechanism-based inactivation of CYP3A4 are furanocoumarins, which bind irreversibly to CYP3A4 and permanently inactivate the isoenzyme. The duration of mechanism based inhibition may be longer than competitive inhibition because new CYP3A4 isoenzymes must be synthesized for activity to be restored. Complete recovery of the CYP3A4 may take 48 to 72 hours after the last exposure to grapefruit juice, which explains why the effects can last for at least 72 hours after drinking grapefruit juice. Most important, because of mechanism-based inhibition, separating the administration of grapefruit juice and substrate drug by a few hours does not minimize grapefruit drug interactions. Pharmacists should advise patients to entirely avoid grapefruit if they are taking medications known to significantly interact with grapefruit juice.
Literature indicated that grapefruit juice at normal volume did not change the terminal half-life (t½) or intravenous pharmacokinetics of drugs. Therefore this pharmacokinetic interaction is thought to be primarily due to grapefruit juice– mediated inhibition of intestinal CYP3A4 activity without apparent inhibition of hepatic CYP3A4 activity. Grapefruit juice inhibition of CYP3A4 in vivo appears to involve irreversible inactivation of CYP3A4, as evidenced by down-regulation of intestinal CYP3A4 protein content without alteration of intestinal messenger ribonucleic acid levels.
The latter mechanism was first noticed when small intestinal biopsy specimens were obtained in healthy volunteers before and after drinking grapefruit juice. With the use of antibodies specific for CYP3A4, it was noted that the intestinal content of CYP3A4 fell by more than 50% after consumption of even a single glass of grapefruit juice. It was then noted that this phenomenon could be reproduced with grapefruit extract or purified DHB in a human intestinal cell line (Caco2) modified to express CYP3A4. Studies performed in these cells have indicated that loss of CYP3A4 in response to DHB exposure is exclusively caused by accelerated degradation of CYP3A4. This is consistent with the observation in humans that grapefruit juice–mediated loss of CYP3A4 protein is not associated with a reduction in CYP3A4 messenger ribonucleic acid
In addition to the effect on CYP3A4, grapefruit juice may also inhibit the drug transporters P-glycoprotein (P-gp) and organic anion transporting peptide (OATP). 3 P-gp is an efflux membrane transporter pump belonging to the adenosine triphosphate-binding cassette family of proteins. As with CYP3A4, P-gp is found in high concentrations within intestinal enterocytes, the primary site of oral drug absorption. The role of P-gp is to actively secrete absorbed drugs back into the intestinal lumen. After uptake by the enterocyte, the drugs are either metabolized by CYP3A4 or pumped back out (effluxed) into the lumen by the P-gp transporter. Therefore, inhibition of CYP3A4 or P-gp will increase blood levels of the drug substrate. Some evidence suggests that active grapefruit components may inhibit intestinal P-gp. 19
A commonly consumed volume (300 ml) of grapefruit juice produced a diminution of oral bioavailability of the drug probes to sufficient magnitude to be pertinent clinically, potentially resulting in reduced benefit of drug. 3, 17
Reduction in bioavailability of certain drugs by grapefruit juice
When a study was conducted to evaluate the effects of grapefruit juice on the pharmacokinetics of the β-adrenergic receptor–blocking agent celiprolol in healthy volunteers the results showed that there was decrease in bioavailability of celiprolol. The grapefruit juice–celiprolol interaction may have been caused by physicochemical factors (eg, an effect on intraduodenal pH and lipid solubility of celiprolol) or formation of a complex between celiprolol and a component of grapefruit juice. However, other mechanisms, such as inhibition of uptake transporters of the intestine, could also have contributed to the interaction. 18 This suggests that grapefruit may also affect in reduction in bioavailability of certain drugs.
Onset, duration and magnitude of effect of grapefruit juice on inhibition of CYP3A4 enzymes
Furanocoumarins are found predominantly in the grapefruit flesh followed by the sac, peel, and seed. The onset of the interaction can occur within 30 minutes following intake of a single glass of grapefruit juice, and the inhibition can last up to 3 days following the last administration of grapefruit juice. The magnitude of inhibition of CYP isoenzymes by grapefruit components appears to be greatest for CYP3A4 and less significant for other CYP isoforms (eg, 1A2, 2C9, and 2C19). Additionally, the interaction appears to affect CYP3A4 in the gut wall to a much greater extent than in the liver. 20
A usual single exposure to grapefruit juice appears to impair the enteric, but not the hepatic component of presystemic extraction of oral midazolam. The time course of recovery from CYP3A4 inhibition after a single exposure to grapefruit juice is not clearly established. Recovery is largely complete within three days, consistent with enzyme regeneration after mechanism-based inhibition. 6’7’-dihydroxybergamottin was verified as a potent mechanism-based inhibitor of some drugs by CYP3A in vitro . 21
Concomitant intake of high amounts of grapefruit juice and the CYP3A4 substrate simvastatin increased the Cmax and AUC(0-∞) of simvastatin and simvastatin acid about 5- to 15-fold. When simvastatin is taken 24 hours after ingestion of grapefruit juice, the extent of the interaction is about 90% smaller than during concomitant administration of simvastatin and grapefruit juice. The interaction potential of even high amounts of grapefruit juice with CYP3A4 substrates dissipates within 3 to 7 days after the last dose of grapefruit juice. 22
Other drugs causing similar interaction
Acute and extended exposure to grapefruit juice produces quantitatively similar inhibition of enteric, but not hepatic, CYP3A. Recovery is complete within 3 days after grapefruit juice discontinuation. Ritonavir greatly inhibits both enteric and hepatic CYP3A. With extended exposure to ritonavir, inhibition is the predominant effect, and recovery to baseline is nearly complete 3 days after ritonavir discontinuation. 17
Within the conditions of this study, the findings suggest that pharmacokinetic and pharmacodynamic drug interactions attributable to inhibition of CYP3A4 are quantitatively far larger and more consistent with ritonavir than with grapefruit juice. Grapefruit juice produces less CYP3A inhibition compared with highly potent inhibitors ritonavir. For this reason ritonavir is commonly used to increase the bioavailbility of other antiretroviral agents such as saquinavir.
Similarly some reports suggest ketoconazole and erythromycin also have a mechanism of action that is similar to grapefruit juice. 2 , 23
Other similar fruits and herbal products which can cause the drug interactions
Seville orange juice is not usually consumed as a juice because of its sour taste, but it is found in marmalade and other jams. 7 When a study was conducted to determine whether Seville orange juice produces a grapefruit juice–like interaction with felodipine and whether bergamottin, DHB, or other furocoumarins are involved. The results suggested that, Seville orange juice and grapefruit juice interact with felodipine by a common mechanism, which is probably inactivation of intestinal CYP3A4. Bergamottin and DHB may be “marker substances” in foods for this interaction. The lack of interaction between Seville orange juice and cyclosporine suggests that grapefruit juice may also inhibit intestinal P-gp, whereas Seville orange juice may selectively “knock out” intestinal CYP3A4. 9, 10
Also, Seville orange juice has been reported to be a possible inhibitor of CYP3A4 enzymes without affecting P-glycoprotein when taken concomitantly with cyclosporine.
Like grapefruit juice, red wine also contains a complex mixture of molecules including flavonoids and other polyphenols. These electron rich molecules are likely substrates for CYP3A4 and may also inhibit the enzyme. Potentially, this inhibition could result in drug interactions. Due to the large consumption of wine world-wide, these interactions could be of great clinical importance.
Responsibility of the pharmacist to bring this issue to public attention
As a widely available fruit source to help meet daily nutritional requirements, grapefruit and grapefruit juice are consumed by many individuals for the fiber, vitamin C, antioxidants, and phytochemicals. For this reason, pharmacists need to understand grapefruit drug interactions as well as common public misinformation, and communicate any potential interaction risks to patients.
The following key messages should be communicated to patients:
- Most medications do not interact with grapefruit juice, but if you consume grapefruit or grapefruit juice let your physician or pharmacist know, especially when beginning a new prescription.
- The effects of OTC products and herbal medications, although believed to be safe based on the current literature, should still be monitored.
- Alternative medications that do not interact with grapefruit may be available if you do not want to stop drinking grapefruit juice or eating grapefruit.
Grapefruit - drug interactions appear to occur only under well-defined circumstances. First, the drug substrate must be predominantly metabolized by CYP3A4. Second, the drug substrate must undergo extensive first-pass metabolism (ie, drugs with low oral bioavailability). Knowledge of these two factors will allow pharmacists to predict whether a medication is likely to interact with grapefruit juice. For example, felodipine has a low oral bioavailability of 15% and is significantly affected by grapefruit juice; whereas amlodipine has a high oral bioavailability of 75% and does not interact with grapefruit juice. Other examples are verapamil and quinine. Grapefruit juice significantly increased plasma concentrations of verapamil (oral bioavailability of 20%) and had no significant effect on the pharmacokinetics of quinine (oral bioavailability of 80%).
The following drugs definitely interact with CYP3A4: (Source www.rxlist.com)
Bupropion, amfebutamone, Wellbutrin (Welbutrin), Paroxetine, paroxetine hydrochloride, Valproate semisodium, divalproex sodium, carbamazepine 24 , digoxin 25 buspirone 26 Benzodiazepines, including: alprazolam, diazepam, midazolam, lorazepam, oxazepam, and chlordiazepoxide.
Additional drugs found to be affected by grapefruit juice include
Statins such as atorvastatin, 27 lovastatin, 28, 29 and simvastatin. Dihydropyridines including felodipine (Plendil), nicardipine, difedipine, nisoldipine, nitrendipine, losartin repaglinide, verapamil, Antiarrhythmics including amiodarone, quinidine Cardioquin, disopyramine, propafenone, and carvediol.
The male impotence drugs sildenafil (Viagra), tadalafil and vardenafil. The anti-migrane drugs ergotamine and nimodipine
Probably Non-Interacting drugs
The following drugs, at least when not interacting with other drugs, are probably safe when consumed with grapefruits: Lamotrigine, Lamictal
Firstly when considering how to manage grapefruit drug interactions, a pharmacist should be competent enough to decide whether the interaction is clinically relevant. A number of medications are reported to have interactions with grapefruit. However many of the other medications have not been proven clinically significant to have interaction. The importance of clearly understanding possible interactions with grapefruit products is becoming more evident.
Secondly, when thinking of substitute for grapefruit juice, there are several other fruit juices available including orange juice as a first choice. Orange juice does not contain responsible components in high concentration, instead containing hesperetin, and may be recommended as a substitute for grapefruit.
Lastly in the recent studies on recovery of the intestinal CYP3A4 enzymes after consuming grapefruit juice suggest that during the clinical trials and pharmacokinetic studies, grapefruit juice should be avoided at least for 72 hours rather than 48 hours or less so that possible inter-subject variability in pharmacokinetic parameters can be reduced. 30
In addition, it is recommended that drugs possibly interacting with grapefruit juice should be appropriately labeled and more studies are needed to clarify interactions involving OTC medications and herbal medications.
- Shiew-Mei Huang, Stephen D. Hall, Paul Watkins, Lori A. Love, Cosette Serabjit-Singh, Joseph M. Betz, Freddie Ann Hoffman, Peter Honig, Paul M. Coates, Jonca Bull, Shaw T. Chen, Gregory L. Kearns, and Michael D. Murray, Drug interactions with herbal products and grapefruit juice: A conference report, Clin Pharmacol Ther 2004;75:1-12.
- J. David Spence, Drug interactions with grapefruit: Whose responsibility is it to warn the public?, Clin Pharmacol Ther 1997;61:395-400.
- George K. Dresser, David G. Bailey, Brenda F. Leake, Ute I. Schwarz, Paul A. Dawson, David J. Freeman, and Richard B. Kim, Fruit juices inhibit organic anion transporting polypeptide–mediated drug uptake to decrease the oral availability of fexofenadine, Clin Pharmacol Ther 2002;71:11-20.
- David G. Bailey, John H. Kreefk, Claudio Munoz, David J. Freeman, and John R Bend, Grapefruit juice-felodipine interaction: Effect of naringin and 6’,7’-dihydroxybergamottin in humans, Clin Pharmacol Ther 1998;64:248-56.
- David J. Edwards, Michael E. Fitzsimmons, Erin G. Schuetz, Kazuto Yasuda, Murray P. Ducharme, Lawrence H. Warbasse, Patrick M. Woster, John D. Schuetz, and Paul Watkins, 6’,7’-Dihydroxybergamottin in grapefruit juice and Seville orange juice: Effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein, Clin Pharmacol Ther, 1999;65:237-44.
- Hugo H. T. Kupferschmidt, Huy Riem Ha, Walter H. Ziegler, Peter J. Meier, and Stephan Krtienbti, Interaction between grapefruit juice and midazolam in humans, Clin Pharmacol Ther 1995;58:20-8.
- Marika Pasternyk Di Marco, David J. Edwards, Irving W. Wainer, <> Murray P. Ducharme, The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: The role of gut CYP3A and P-glycoprotein Life Sciences 71 (2002) 1149–1160
- Theunis C. Goosen, Doré Cillié, David G. Bailey, <> Chongwoo Yu Kan He, Paul F. Hollenberg, Patrick M. Woster, Lucinda Cohen, J. Andrew Williams, Malie Rheeders, Bergamottin contribution to the grapefruit juice–felodipine interaction and disposition in humans, Clin Pharmacol Ther, 2004; 76:607-17.
- Shefali M. Kakar, Mary F. Paine, Paul W. Stewart, and Paul B. Watkins, 6'7'-Dihydroxybergamottin contributes to the grapefruit juice effect, Clin Pharmacol Ther , 2004; 75:569-79.
- Shefali Malhotra, BS, David G. Bailey, Mary F. Paine, and Paul B. Watkins, Seville orange juice-felodipine interaction: Comparison with dilute grapefruit juice and involvement of furocoumarins, Clin Pharmacol Ther 2001;69:14-23.
- K. Fukuda, Lianqing Guoa, Noriko Ohashib, Masayoshi Yoshikawab, Yasushi Yamazoe J., Amounts and variation in grapefruit juice of the main components causing grapefruit–drug interaction, Chromatogr. B 741 (2000) 195 –203.
- Tomihisa Ohta, Takuro Maruyama, Minoru Nagahashi, Yasuyo Miyamoto, Shinzo Hosoi, Fumiyuki Kiuchi, Yasushi Yamazoe and Sachiko Tsukamoto, Paradisin C: a new CYP3A4 inhibitor from grapefruit juice, Tetrahedron 58 (2002) 6631–6635.
- Bruno Tirillini, Grapefruit: the last decade acquisitions, Fitoterapia 71(2000) S29-S37.
- David G. Bailey, John H. Kreefk, Claudio Munoz, David J. Freeman, and John R Bend, Grapefruit juice-felodipine interaction:Effect of naringin and 6’,7’-dihydroxybergamottin in humans, Clin Pharmacol Ther 1998;64:248-56.
- William K. Ghan, Lot T. Nguyen’, Vaughn P. Miller, and Robert Z. Harris, Mechanism-based inactivation of human cytochrome P450 3A4 by grapefruit juice and red wine, Pharmacology Letters , Vol. 62, No. 10, 1998.
- Hugo H. T. Kupferschmidt, Huy Riem Ha, Walter H. Ziegler, Peter J. Meier, and Stephan Krtienbti, Interaction between grapefruit juice and midazolam in humans.
- Kerry E. Culm-Merdek, Lisa L. von Moltke, Lu Gan, Kelly A. Horan, Robyn Reynolds, Jerold S. Harmatz, Michael H. Court , and David J. Greenblatt, Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: Comparison with ritonavir, Clin Pharmacol Ther 2006; 79:243-54.
- Jari J. Lilja, Janne T. Backman, Jouko Laitila, Harri Luurila, and Pertti J. Neuvonen, Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol, Clin Pharmacol Ther 2003;73:192-8.
- Ute I. Schwarz, Diana Seemann, Reinhard Oertel, Stephan Miehlke, Eberhard Kuhlisch, Martin F. Fromm, Richard B. Kim, David G. Bailey, and Wilhelm Kirch, Grapefruit juice ingestion significantly reduces talinolol bioavailability, Clin Pharmacol Ther 2005;77:291-301.
- Mary F. Paine, Anne B. Criss, and Paul B. Watkins, Two Major Grapefruit Juice Components Differ in Time to Onset of Intestinal CYP3A4 Inhibition, The Journal Of Pharmacology And Experimental Therapeutic, 312:1151–1160, 2005.
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- Jari J. Lilja, Kari T. Kivistö, and Pertti J. Neuvonen, Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin, Clin Pharmacol Ther , 2000;68:384-90.
- Anas Saadeddin, Francisca Torres-Molina, Jaime Cárcel-Trullols, Amparo Araico, José Esteban Peris, Effect of cytochrome P450 inhibitors (diethyl dithiocarbamate, ketoconazole and grapefruit juice) on the pharmacokinetics of all-trans-retinoic acid, Il Farmaco , 59 (2004) 697–702.
- Santosh K. Garg, Naresh Kumar, Vinod R Bhargava, and Sudesh K. Prabhakar, Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy, Clin Pharmacol Ther 1998; 64:286-8.
- Laurent Becquemont, C&line Verstuyft, Reinhold Kerb, Ulrich Brinkmann, Martine Lebot, Patrice Jaillon, and Christian Funck-Brentano, Effect of grapefruit juice on digoxin pharmacokinetics in humans, Clin Pharmacol Ther 2001;70:311-6.
- Jari J. Lilja, Kari T. Kivistii, Janne T. Backman, Tommi S. Lamberg, and Pertti J. Neuvonen, Grapefruit juice substantially increases plasma concentrations of buspirone, Clin Pharmacol Ther 1998;64:655-60.
- Jari J. Lilja, Kari T. Kivistö, and Pertti J. Neuvonen, Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin, Clin Pharmacol Ther 1999;66:118-27.
- Teemu Kantola, Kari T. Kivistii, and Pertti J. Neuvonen, Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid, Clin Pharmacol Ther 1998; 63:397-402.
- John D. Rogers, Jamie Zhao, Lida Liu, Raju D. Amin, BS, Kathleen D. Gagliano, Arturo G. Porras, Robert A. Blum, Michael F. Wilson, Michael Stepanavage, and Jose M. Vega, Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, Clin Pharmacol Ther 1999;66:358-66.
- Amyl Stump, Terri Mayo, and Alan Blum, Management of Grapefruit-Drug Interactions, Am Fam Physician, 2006; 74:605-8, 611.
Prasad Tandale * , Meena C and Gaud R S, School of Pharmacy and Technology management, Narsee Monjee Institute of Management and Higher Studies (Deemed University), V.L. Mehta Road , Vile Parle (W), Mumbai – 400 056, INDIA