Grapefruit
Grapefruit/Drug Interactions:
NoteNote: Grapefruit affects the activities of many drugs, with potentially serious effects. Interactions with various drugs (prescription or over-the-counter) can occur when using any part or form of grapefruit, including grapefruit juice or peel. Patients taking prescription drugs who are considering using a product that contains grapefruit are encouraged to talk with their healthcare providers or pharmacists. Some examples are below.AcebutololAcebutolol: Grapefruit juice has caused a decrease in plasma concentrations of acebutolol and diacetolol by interfering with gastrointestinal absorption (37). In a randomized crossover study, grapefruit juice decreased the Cmax of acebutolol by 19% (p<0.05) and the AUC by 7% (p<0.05) (37). The t? of acebutolol prolonged from 4.0 to 5.1 hours (p<0.05). The time to peak concentration and the amount of acebutolol excreted into urine (Ae) were unchanged. The Cmax, AUC(0-33 hours), and Ae of diacetolol (metabolite) were decreased by 24% (p<0.05), 18% (p<0.05), and 20% (p<0.01), respectively, by grapefruit juice. These decreases in plasma concentrations by grapefruit juice were likely caused by interfering with gastrointestinal absorption. AlprazolamAlprazolam: There is a lack of human evidence supporting an interaction between grapefruit and alprazolam (14). AmlodipineAmlodipine: Grapefruit has no appreciable effect on amlodipine pharmacokinetics or pharmacodynamics, including its stereoselective kinetics, probably because it has a lower first pass metabolism and higher oral bioavailability relative to other dihydropyridine calcium antagonists (38). The increase in amlodipine plasma concentration after the intake of grapefruit juice was too small to significantly affect blood pressure or heart rate (39). AmprenavirAmprenavir: Clinical study shows that grapefruit juice led to small changes in pharmacokinetic parameters (Cmax and tmax) (40). Analgesics, narcoticAnalgesics, narcotic: Theoretically, the ability of grapefruit to inhibit CYP3A4 may lead to delayed recovery from anesthesia when these agents are used for this purpose.Anthelmintics (e.g. praziqauntel)Anthelmintics (e.g. praziqauntel): Based on a human study, grapefruit may increase side effects associated with anthelmintics, especially praziquantel (41). The biotransformation of praziquantel appeared to be mediated mainly by CYP3A4 and the increase in the bioavailability of praziquantel in this study suggested that it may be metabolized in the small intestine. Antianxiety drugsAntianxiety drugs: Grapefruit may increase the side effects associated with anxiolytics, such as benzodiazepines (42; 43; 44; 45; 46; 47; 48; 49; 50). Antiarrhythmic agentsAntiarrhythmic agents: Grapefruit may interact with antiarrhythmic drugs (e.g., amiodarone, propafenone, and quinidine) through the intestinal CYP450 3A4 system (51; 52; 53). Grapefruit juice completely inhibited the production of N-DEA, the major metabolite of amiodarone, in a human study (51). This inhibition of N-DEA production led to increases in the AUC by 50% and a decrease in the alterations caused by amiodarone on PR and QTc intervals (51). Administration of 240mL of grapefruit juice was found to delay the absorption of 400mg quinidine and inhibit the metabolism of quinidine to 3-hydroxyquinidine in one study of 12 male participants (54). A 33% decrease in the AUC of 3-hydroxyquinidine was reported, but there were no increases in the AUC of quinidine or change in the ratio of AUC of 3-hydroxyquinidine to the AUC of quinidine (54). An in vivo study found that 250mL grapefruit juice twice daily reduced the total clearance of quinidine and its partial clearance by 3-hydroxylation and N-oxidation by 15, 19, and 27%, respectively; the elimination half-life of quinidine was increased by 19% (52). AntibioticsAntibiotics: The bioavailability of erythromycin was increased by the inhibitory effect of grapefruit juice on CYP450 3A4-mediated metabolism in the small intestine. Six men received 400mg erythromycin with either water or grapefruit juice. Grapefruit juice, compared with water intake, significantly (p<0.05) increased the mean Cmax value (1.65 ? 0.94 vs. 2.51 ? 0.68mcg/mL) and the mean AUC(0-12) value of erythromycin (5.92 ? 3.25 vs. 8.80 ? 1.32MCg.h/mL) (33). However, time to reach maximum serum concentration (tmax) and elimination half-life were not affected. In another trial of 12 participants, the administration of one glass of grapefruit juice increased the time to peak concentration of clarithromycin (500mg dose) from approximately 82 minutes to 148 minutes but did not affect any other pharmacokinetic parameters (55). On the contrary, grapefruit juice did not alter pharmacokinetic parameters when administered with telithromycin 800mg daily (56). Anticoagulants and antiplateletsAnticoagulants and antiplatelets: Grapefruit may increase the risk of bleeding when used with anticoagulant or antiplatelet medications (57). Grapefruit juice decreased the urinary excretion of 7-hydroxycoumarin after oral administration of 10mg coumarin for up to eight hours after simultaneous intake (58). It appears that grapefruit flavonoids inhibit cytochrome P450 2A dependent metabolic pathways, but the mechanism of this inhibition is not understood. Anticonvulsant agentsAnticonvulsant agents: Based on human study, grapefruit may increase the bioavailability of some anticonvulsants (59), but not all of them (11). Antidepressant agents (SSRIs, MAOIs)Antidepressant agents (SSRIs, MAOIs): Based on in vitro, in vivo, and preliminary human study, grapefruit may inhibit the metabolism of antidepressants (60; 61). Antidiabetic agentsAntidiabetic agents: Based on pharrmacokinetics, grapefruit and grapefruit juice may raise blood glucose and may theoretically alter the effects of antidiabetic agents (62; 63; 64). AntifungalsAntifungals: Based on human study, grapefruit may reduce the effectiveness of antifungal agents, such as itraconazole, possibly by presystemic intestinal metabolism via CYP3A4 (65), although the effects are unclear (66). AntihistaminesAntihistamines: Based on in vitro and human study, grapefruit may increase the bioavailability and side effects associated with antihistamines (67; 68; 69; 70; 71; 72; 73). Antilipemic agents, HMG-CoA reductase inhibitorsAntilipemic agents, HMG-CoA reductase inhibitors: HMG-CoA reductase inhibitors are known to interact with grapefruit (74). Grapefruit may increase the Cmax and AUC of these agents (75; 76; 77; 78; 79; 80; 81; 12; 34; 82; 53; 83). Antimalarial agentsAntimalarial agents: Grapefruit juice has been shown to increase Cmax and AUC of antimalarial agents such as artemether, halofantrine, and primaquine (84; 85; 86; 87). Halofantrine is metabolized into N-debutyl-halofantrine by CYP450 3A4. In a randomized crossover study, grapefruit juice increased halofantrine bioavailability and halofantrine-induced QT interval prolongation. Compared with water, grapefruit juice increased halofantrine AUC and peak plasma concentration by 2.8-fold ? 1.5-fold (p<0.0001) and 3.2-fold ? 1.3-fold (p<0.0001), respectively (84). Grapefruit juice significantly (p=0.001) increased Cmax of artemether more than two-fold from 42ng/mL to 107ng/mL. The tmax with grapefruit juice was 2.1 hours. The AUC almost doubled with grapefruit juice from 177ng.hour/mL to 336ng.hour/mL (p=0.003). The elimination half-life remained unchanged (1.0 hours vs. 1.3 hours). No signs of bradycardia or QTc prolongation were observed with coadministration of artemether and grapefruit juice (86). Results suggested that CYP3A4 in the gut wall is one of the metabolizing enzymes of artemether (86; 87).Grapefruit juice has been found to have no effect on quinine pharmacokinetics (9). Grapefruit juice increased the bioavailability of primaquine, with marked interindividual differences (85). Antineoplastic agentsAntineoplastic agents: Grapefruit may reduce the effectiveness of antineoplastic agents, based on human and in vivo studies (88; 73; 89). Antipsychotic agentsAntipsychotic agents: Antipsychotic drugs, such as clozapine and haloperidol, have not been shown to be altered by grapefruit ingestion in human studies (90; 91; 92; 93). Antiretroviral agents, protease inhibitorsAntiretroviral agents, protease inhibitors: Based on clinical studies, grapefruit may increase the bioavailability and adverse effects of protease inhibitors (94; 40; 95; 96; 97; 98). AripiprazoleAripiprazole: According to the manufacturer of aripiprazole, due to the ability of grapefruit to inhibit CYP3A4, the levels/effects of aripiprazole may be increased, and it is recommended that the dose of aripiprazole be decreased by 50%.BenzodiazepinesBenzodiazepines: When co-administered with grapefruit juice a slight increase in the effects of benzodiazepines, such as triazolam and midazolam, have been observed (42; 43; 94; 44; 45; 46; 47; 48; 99; 49; 50). The effects of grapefruit juice on the pharmacodynamics of triazolam may be greater than those on quazepam. These grape fruit juice-related different effects are partly explained by the fact that triazolam is presystemically metabolized by CYP3A4, while quazepam is presystemically metabolized by CYP3A4 and CYP2C9 (99). Beta blockersBeta blockers: Grapefruit juice has caused decreases in concentrations of beta-blocking agents (37; 100; 101). Grapefruit juice greatly decreased the Cmax and AUC values of celiprolol (100), reduced talinolol bioavailability (101), decreased talinolol transport from basolateral to apical side and may have a high potential in the interaction with P-gp-mediated talinolol transport in Caco-2 cells (74), and increased triazolam area under the plasma concentration curve, without altering half-life (94). BudesonideBudesonide: Based on unsubstantiated sources, grapefruit juice intake may increase systemic availability of budesonide, probably by inhibition of intestinal CYP3A4 activity.BuspironeBuspirone: Based on the pharmacokinetics of grapefruit juice, there may be an interaction with buspirone (102). CaffeineCaffeine: Clinical studies have shown that the ingestion of grapefruit juice should not cause any pharmacokinetic or pharmacodynamic interactions when coadministered with caffeine (103; 104; 105). Calcium channel blockersCalcium channel blockers: Grapefruit may increase the adverse effects associated with some calcium channel blockers (106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 31; 117; 118; 119; 120; 121; 122; 123; 124; 125; 126; 127; 13; 128; 53; 129; 130; 131). The basis for this interaction appears to relate to both flavanoid and nonflavanoid components of grapefruit juice interfering with enterocyte CYP3A4 activity. In the process, presystemic clearance of susceptible drugs decreases and bioavailability increases. CarbamazepineCarbamazepine: Grapefruit juice increases the bioavailability of carbamazepine by inhibiting CYP450 3A4 enzymes in the gut wall and in the liver (59). CyclosporineCyclosporine: Animal and human studies have reported increased blood levels of cyclosporine when taken with grapefruit (132; 133; 134; 135; 10; 136; 137; 138; 139; 140). It has been reported that 6',7'-dihydroxybergamottin, a furanocoumarin found in grapefruit, is not responsible for the effects of grapefruit juice on cyclosporine; the inhibition of P-glycoprotein activity by other compounds in grapefruit juice may be responsible (134). It has been reported that grapefruit juice increased AUC of cyclosporine in African American subjects by 60%, while grapefruit juice increased that in Caucasian subjects by 44% (138). Cytochrome P450 metabolized agentsCytochrome P450 metabolized agents: Preliminary evidence suggests that grapefruit juice may inhibit cytochrome P450 1A2 (30), cytochrome P450 2C9 (99; 30), or cytochrome P450 2C19 (30). Currently, these interactions have not been reported in humans. Grapefruit juice can inhibit CYP3A4 metabolism of drugs, causing increased drug levels and potentially increasing the risk of adverse effects (75; 64; 94; 141; 142; 31; 143; 144; 32; 33; 12; 34; 145; 146; 147; 148; 127; 53; 99; 131). DextromethorphanDextromethorphan: Grapefruit juice can inhibit cytochrome P450 3A4 metabolism, causing increased dextromethorphan levels and potentially increasing the risk of adverse effects (149). DigoxinDigoxin: Modest changes in digoxin pharmacokinetics have been observed following digoxin administration (150; 151). Inhibition of intestinal P-glycoprotein does not appear to play an important role in drug interactions involving grapefruit juice and digoxin. DiltiazemDiltiazem: There is conflicting data regarding the interaction between grapefruit and diltiazem. Grapefruit juice intake did not alter the AUC, Cmax, or tmax of diltiazem nor N-demethyldiltiazem nor deacetyldiltiazem (152). Among the grapefruit juice treatment and the control values of the mean arterial pressure, heart rate, and PR-interval, no statistically significant differences were found. However, in a different randomized crossover study, administration of diltiazem with grapefruit juice compared with water significantly increased AUC (0-24) of diltiazem by an average individual increase of 20 ? 25% compared with water. The average individual increase in Cmax of diltiazem after grapefruit juice administration was 22 ? 37%, but this effect was not statistically significant (p=0.14). The terminal half-life was not affected by grapefruit juice. Inhibition of intestinal metabolism and/or P-glycoprotein efflux transport may be responsible for this effect (112). EletriptanEletriptan: Theoretically, grapefruit juice may inhibit cytochrome P450 3A4 metabolism, causing increased eletriptan levels and potentially increasing the risk of adverse effects.EplerenoneEplerenone: According to the manufacturer, grapefruit juice increases eplerenone AUC 25%, which may result in an increased risk of adverse events including hyperkalemia and serious arrhythmias.Ergot derivativesErgot derivatives: Theoretically, grapefruit juice may decrease ergot metabolism via the inhibition of CYP3A4.Estrogen and progestin combinationEstrogen and progestin combination: Grapefruit may increase the bioavailability and side effects associated with estrogen (153; 154; 155). In one randomized crossover trial, grapefruit juice increased the ethinylestradiol Cmax significantly to 137% (p=0.0088) and increased the AUC(0-8) to 128% (p=0.0186) (155). Grapefruit juice has demonstrated the ability to alter the metabolic degradation of estrogens and increase the bioavailable amounts of 17beta-estradiol and its metabolite estrone in ovariectomized women (154). The most likely mechanism of action of the flavonoids of grapefruit juice on 17 beta-estradiol metabolism is the inhibition of the CYP450 3A4 enzyme, which catalyzes the reversible hydroxylation of 17 beta-estradiol into estrone and further into estriol (154). EszopicloneEszopiclone: Grapefruit juice can inhibit cytochrome P450 3A4 metabolism and theoretically may increase eszopliclone levels and potentially increase the risk of adverse effects.EtoposideEtoposide: From a crossover human study, there is some evidence that grapefruit juice coadministered with oral etoposide can reduce the AUC of etoposide on average by 26.2% (88). FelodipineFelodipine: The oral felodipine administration concomitantly with grapefruit juice was connected with a significant increase of hemodynamic effects. Clinical studies showed that grapefruit juice has a moderate interaction with felodipine (109; 113; 111; 108; 107; 113; 114; 116; 124; 125; 126). The mean AUC and Cmax of felodipine were increased around 1.5- to 3-fold (106; 110; 113; 144; 146). It seems that bergamottin is not solely responsible for the effect of grapefruit juice on the pharmacokinetics of felodipine (109). Furanocoumarins are active ingredients in grapefruit and may be responsible for enhancing the systemic exposure of felodipine and probably other CYP3A4 substrates that undergo extensive intestinal first-pass metabolism (146). Since the duration of effect of grapefruit juice can last 24 hours, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax (106). FexofenadineFexofenadine: Grapefruit may reduce the effectiveness of antihistamines such as fexofenadine (67; 156). In an in vitro study, grapefruit juice inhibited absorption of fexofenadine by interacting with P-glycoprotein in the intestinal tract (73). One randomized crossover study found that the 300mL of grapefruit juice decreased the mean AUC and the peak plasma drug concentration of fexofenadine to 58% (p<0.001) and 53% (p<0.001), respectively (70). HaloperidolHaloperidol: No pharmacokinetic interaction was observed between haloperidol and grapefruit juice (93). Grapefruit juice did not alter total or subgroup scores of BPRS (brief psychiatric rating scale) or UKU (Udvalg for kliniske underosgelser) side effect rating throughout the study. Plasma concentrations of haloperidol and reduced haloperidol during grapefruit juice treatment were not significantly different from those before grapefruit juice treatment or those one-week after its discontinuation. In accordance with the negative results regarding plasma concentrations of haloperidol and reduced haloperidol, the clinical effects of haloperidol were unchanged throughout the study. Therefore, grapefruit juice is probably safe for patients treated with haloperidol. ImatinibImatinib: According to the manufacturer, grapefruit juice may inhibit CYP3A4 metabolism of imatinib in the intestinal wall, possibly resulting in increased drug levels and risk of adverse events.ImmunosuppressantsImmunosuppressants: Based on animal and human studies, grapefruit may increase absorption and plasma concentrations of immunosuppressants; however the mechanism of action is unclear (132; 133; 134; 157; 135; 10; 136; 137; 138; 140; 158; 159; 53). Grapefruit may increase side effects associated with immunosuppressants. Increased levels of cyclosporine, methylprednisolone, and tacrolimus have been reported when taken with grapefruit (132; 133; 134; 157; 135; 10; 136; 137; 138; 158; 140). Impotence agentsImpotence agents: Grapefruit has been shown to modestly increase the absorption of sildenafil (32; 160). The AUC of sildenafil was increased by 23% by grapefruit juice, but the Cmax of sildenafil was unchanged (32). Theoretically, grapefruit may have similar effects if used with other erectile dysfunction agents. IndinavirIndinavir: Grapefruit has not been shown to significantly affect the bioavailability of indinavir (97; 98). LansoprazoleLansoprazole: No effect of grapefruit juice was observed on the mean maximum plasma concentrations (Cmax) or the elimination half-life for each lansoprazole enantiomer in all three CYP2C19 genotype groups (145). LevothyroxineLevothyroxine: Grapefruit juice may slightly delay the absorption of levothyroxine, but it seems to have only a minor effect on its bioavailability (161). Accordingly, the clinical relevance of the grapefruit-levothyroxine interaction is likely to be small. LosartanLosartan: Concomitant use of grapefruit juice and losartan may reduce the effectiveness of losartan, but further study is necessary to confirm these findings. Losartan is an inactive prodrug that must be metabolized to its active form, E-3174, by CYP 3A4 and 2C9 to be effective. In one human study, grapefruit juice reduced losartan metabolism, increased losartan AUC, and reduced the AUC of the major active losartan metabolite, E-3174, which was considered indicative of simultaneous CYP 3A4 inhibition and P-glycoprotein activation (162). LovastatinLovastatin: Grapefruit juice can increase serum concentrations of lovastatin and its active metabolite, lovastatin acid, probably by preventing CYP3A4-mediated first-pass metabolism in the small intestine (79). In one randomized crossover study, grapefruit juice increased Cmax about 12-fold and the AUC(0-12) about 15-fold (79). MethylprednisoloneMethylprednisolone: Grapefruit juice may increase plasma concentration of orally administered methylprednisolone. Grapefruit juice 200mL three times daily given with methylprednisolone 16mg increased methylprednisolone half-life by 35%, Cmax by 27%, and total AUC by 75% (158). MethylxanthinesMethylxanthines: Grapefruit juice seems to modestly decrease theophylline levels when given concurrently with sustained-release theophylline (163). The mechanism of action is not understood. MidazolamMidazolam: In one study of 25 health volunteers, the AUC for midazolam increased by a factor of 1.65 (ratio compared with control) when midazolam was given two hours after grapefruit juice (44). The midazolam elimination half-life did not change significantly from the control value at any time after grapefruit juice exposure. Grapefruit juice (8 oz) increased midazolam Cmax and AUC by a factor of 1.3 and 1.5, respectively, and reduced oral clearance to 72% of control values (142). MifepristoneMifepristone: Theoretically, grapefruit juice may inhibit mifepristone metabolism via cytochrome P450 3A4, resulting in increased drug levels and associated adverse events.Neurologic agentsNeurologic agents: Grapefruit may interact with neurologic agents. For instance, grapefruit may increase the side effects associated with anxiolytics, such as benzodiazepines (42; 43; 44; 45; 46; 47; 48; 49; 50). Grapefruit may inhibit the metabolism of antidepressants (60; 61) and increase the side effects associated with tricyclic antidepressants (61). NicotineNicotine: Grapefruit juice was found to inhibit the metabolism of nicotine to cotinine, a pathway mediated by CYP2A6, and increase the renal clearance of nicotine and cotinine. Nicotine oral clearance was not affected by grapefruit juice because the inhibition of hepatic metabolism was offset by the increase in the renal clearance of nicotine. However, other compounds metabolized by CYP2A6, as well as other drugs excreted via renal clearance mechanisms similar to those of nicotine may be susceptible to significant pharmacokinetic grapefruit juice interactions (164). NifedipineNifedipine: Clinical studies show that grapefruit juice has a weak interaction with nifedipine-containing drugs and increases the AUC and Cmax (107; 117; 119; 115; 129; 126; 13). In one randomized crossover study, grapefruit juice increased the AUC by an average of 10.3% compared with water. Grapefruit juice interferes with the metabolism of nifedipine by inhibiting nifedipine metabolism and slowing down the rate of gastric emptying. Metabolic inhibition may be a first pass effect, but it is a secondary oxidative step (115). NimodipineNimodipine: A clinical study shows that the coadministration of grapefruit juice and nimodipine increased the Cmax for nimodipine to 124% of the reference period and AUC to 151% (121). NitrendipineNitrendipine: The AUC of racemic nitrendipine with grapefruit juice was increased (mean increase 106%) compared to that with placebo treatment (128). Grapefruit juice did not have significant additional effects on any of the hemodynamic parameters. OpiatesOpiates: Theoretically, grapefruit may interfere with the metabolism of opioids by the liver and small intestine cytochrome P450 3A4 enzyme. Grapefruit has been shown to increase the bioavailability of methadone (165; 166). In one study of eight patients undergoing methadone maintenance treatment, grapefruit juice led to a mean 17% increase in AUC(0-24) for both enantiomers of methadone (165). Grapefruit juice was not associated with any change in the intensity of withdrawal symptoms by the patients (165). OxybutyninOxybutynin: Theoretically, grapefruit juice may inhibit the hepatic metabolism of oxybutynin leading to increased drug levels and associated adverse events.P-glycoprotein regulated drugsP-glycoprotein regulated drugs: Inhibition of P-glycoprotein activity by other compounds in grapefruit juice may be responsible for interactions and may interfere with P-glycoprotein regulated drugs (134; 74). PhenytoinPhenytoin: On the contrary, grapefruit juice did not alter the oral bioavailability of phenytoin 300mg in one study using a single dose in 10 men (11). PimozidePimozide: Based on unsubstantiated sources, pimozide serum concentration may be increased when taken with grapefruit juice due to cytochrome P450 3A4 inhibition, which may result in an increased risk of adverse events including QT prolongation and cardiac arrhythmias.PrimaquinePrimaquine: Grapefruit juice increased the bioavailability of primaquine, with marked interindividual differences (85). Concomitant use should be avoided. Prednisone, prednisolonePrednisone, prednisolone: Grapefruit juice was found to have no significant effect on the metabolism of prednisone or prednisolone in one study of kidney transplant patients (10). Prokinetic agentsProkinetic agents: Grapefruit juice has been shown to significantly increase plasma concentration of cisapride, probably by the inhibition of cytochrome P450 3A4-mediated first pass metabolism of cisapride in the small intestine (167). In a randomized crossover study, the mean peak plasma concentration of cisapride was increased by 81% and the AUC by 144% by grapefruit juice (167). Other studies confirmed the findings that grapefruit juice increases the oral bioavailability of cisapride with large interindividual variation in the change in Cmax and AUC (168; 169). As cisapride has a wide therapeutic index, the interaction may not be of clinical significance for efficacy (170). RanolazineRanolazine: According to the manufacturer, grapefruit juice should be avoided in patients taking ranolazine due to the ability of grapefruit juice to inhibit cytochrome P450 3A4, resulting in possible QT prolongation and cardiac arrhythmias.RepaglinideRepaglinide: Neither the mean AUC(0-infinity) (geometric mean ratio: 1.01; 95% CI: 0.93-1.1, p=0.88) nor the mean Cmax (geometric mean ratio: 1.05; 95% CI: 0.94-1.2, p=0.35) of repaglinide were statistically significantly different in the group carrying the CYP2C8*3 mutant allele compared with wild-types. Grapefruit juice caused a 19% decrease in the geometric mean ratio of the 3-hydroxyquinidine to quinidine ratio (difference: 0.81; 95% CI: 0.75-0.87, p<0.0001), which was used as an index of CYP3A4 activity, and an increase in the mean AUC(0-infinity) of repaglinide (geometric mean ratio: 1.13; 95% CI: 1.04-1.2, p=0.0048), but had no statistically significant effect on the t(1/2). There was no statistically significant difference in blood glucose concentration in subjects who had or had not ingested grapefruit juice. The effect was more pronounced at the low dose of repaglinide (0.25mg) than at the therapeutic dose of 2mg (64). SaquinavirSaquinavir: Grapefruit has been shown to increase the AUC of saquinavir (95; 96). In one study of eight healthy volunteers, the oral bioavailability of saquinavir increased by a factor of two with grapefruit juice (from 0.7% to 1.4%) (96). The study demonstrated that grapefruit juice may increase the bioavailability of saquinavir without affecting its clearance, suggesting that the inhibition of intestinal CYP3A4 may contribute. ScopolamineScopolamine: A clinical study showed that the AUC was increased to 30% when scopolamine was administered with grapefruit juice; tmax and half-life were also increased (171). This interaction is likely due to CYP3A4 inhibition in the intestine. SimvastatinSimvastatin: Clinical studies show that grapefruit increases plasma levels of simvastatin (77; 80; 81; 34; 83). The mean increase in simvastatin AUC was 3.6-fold and the increase in mean Cmax was 3.9-fold (80). SunitinibSunitinib: According to the manufacturer, grapefruit juice may inhibit CYP3A4 metabolism of sunitinib in the intestinal wall, possibly resulting in increased drug levels and risk of adverse events.TacrolimusTacrolimus: The bioavailability of tacrolimus was doubled when it was coadministered with the CYP3A4 inhibitor - ketoconazole (157). There is a case of a living-donor liver transplant recipient experiencing a considerable increase in the trough blood concentration of tacrolimus after concomitant ingestion of grapefruit juice (250mL) four times for three days (159). TerfenadineTerfenadine: The administration of grapefruit juice concomitantly with terfenadine may lead to an increase in terfenadine bioavailability and increase the risk of cardiotoxicity (69; 72; 68). A randomized crossover trail investigated the effects of grapefruit juice on terfenadine. Cmax was higher (72). Terfenadine carboxylate AUC, Cmax, and tmax were also increased but t? was not altered. Another study involving six healthy volunteers reported a significant increase in the AUC of terfenadine by concomitant grapefruit administration (median values 40.6 vs. 16.3ng.mL-1.h) and the Cmax (median values 7.2 vs. 2.1ng/mL); the tmax was not significantly increased and there was no significant change in the median QTc interval despite the increased terfenadine levels (69). The mechanism likely involved reduced presystemic drug elimination by inhibition of more than one metabolic pathway (72; 68). TolterodineTolterodine: Theoretically, grapefruit juice may increase the serum level and/or toxicity of tolterodine, but unlikely secondary to high oral bioavailability.TrazodoneTrazodone: Trazadone is metabolized in vivo by CYP450 3A4 and theoretically may interact with grapefruit juice; however, such an interaction is unlikely. Trazadone has a high oral bioavailability ranging between 60% and 70% and any intestinal metabolism and possible inhibition by grapefruit juice are probably insignificant.TriazolamTriazolam: One glass of grapefruit juice increased plasma triazolam concentrations (AUC was increased by 53%; Cmax was increased by about 40%) in a randomized crossover study of 12 volunteers (48). The t? of triazolam was prolonged by repeated consumption of grapefruit juice, probably due to the inhibition of hepatic CYP3A4 activity. VerapamilVerapamil: Daily intake of grapefruit juice with verapamil increased the AUC and Cmax (31; 118; 123). In a randomized crossover study, grapefruit juice significantly increased the AUC(0-12) of S-verapamil by 36% (118). The AUC(0-12) of R-verapamil was increased by 28%. Elimination half-life and renal clearance of both S- and R-verapamil were not affected. There were no significant differences in the pharmacodynamic parameters (BP, HR and PR-interval). Verapamil has a relatively low therapeutic index and there was a considerable inter-individual variability in the interaction. CYP450 3A4 inhibition in the gut wall contributed to this interaction. VinblastineVinblastine: Grapefruit has been shown in in vitro study to inhibit the absorption of vinblastine by interacting with P-glycoprotein in the intestinal tract (73). VincristineVincristine: Grapefruit juice bioflavonoids have been shown in in vivo study to alter the permeation of vincristine across the blood-brain barrier (89). ZaleplonZaleplon: Zaleplon is at least partially metabolized by CYP3A4 and given its low oral bioavailability, it theoretically may interact with grapefruit.ZolpidemZolpidem: Zolpidem is metabolized in vivo by CYP3A4 and theoretically may interact with grapefruit; however, such an interaction is unlikely. Zolpidem has a high oral bioavailability and any intestinal metabolism and possible inhibition by grapefruit juice are probably insignificant.Grapefruit/Herb/Supplement Interactions:
NoteNote: Grapefruit affects the activities of many herbs or supplements, with potentially serious effects. Interactions with various herbs or supplements can occur when using any part of the grapefruit, including grapefruit juice or peel. Patients taking herbs or supplements who are considering using a product that contains grapefruit are encouraged to talk with their healthcare providers or pharmacists. Some examples are below.AnalgesicsAnalgesics: Theoretically, the ability of grapefruit to inhibit CYP3A4 may lead to delayed recovery from anesthesia when these agents are used for this purpose.AntiarrhythmicsAntiarrhythmics: Theoretically, grapefruit may increase the adverse effects associated with antiarrhythmic herbs and supplements. Grapefruit juice completely inhibited the production of N-DEA, the major metabolite of amiodarone (51). This inhibition of N-DEA production led to a decrease in the alterations caused by amiodarone on PR and QTc intervals. AntibacterialsAntibacterials: The bioavailability of erythromycin was increased by the inhibitory effect of grapefruit juice on CYP450 3A4-mediated metabolism in the small intestine. Six men received 400mg erythromycin with either water or grapefruit juice. Grapefruit juice, compared with water intake, significantly (p<0.05) increased the mean Cmax value (1.65 ? 0.94 vs. 2.51 ? 0.68mcg/mL) and the mean AUC(0-12) value of erythromycin (5.92 ? 3.25 vs. 8.80 ? 1.32mcg.h/mL) (33). However, time to reach maximum serum concentration (tmax) and elimination half-life were not affected. In another trial of 12 participants, administration of one glass of grapefruit juice increased the time to peak concentration of clarithromycin (500mg dose) from approximately 82 minutes to 148 minutes but did not affect any other pharmacokinetic parameters (55). On the contrary, grapefruit juice did not alter pharmacokinetic parameters when administered with telithromycin 800mg daily (56) Anticoagulants and antiplateletsAnticoagulants and antiplatelets: Theoretically, grapefruit may increase the risk of bleeding when used with anticoagulant or antiplatelet herbs or supplements (57), such as Ginkgo biloba, chamomile, danshen, etc. Grapefruit juice decreased the urinary excretion of 7-hydroxycoumarin after oral administration of 10mg coumarin for up to eight hours after simultaneous intake (58). It appears that grapefruit flavonoids inhibit cytochrome P450 2A dependent metabolic pathways, but the mechanism of this inhibition is not understood. AnticonvulsantsAnticonvulsants: Theoretically, grapefruit may increase side effects associated with anticonvulsant herbs and supplements. Grapefruit juice has been found to increase the bioavailability of carbamazepine in one study of 10 patients with epilepsy who had received therapy with 200mg carbamazepine three times per day for three to four weeks prior to the trial period (59). Antidepressants, selective serotonin reuptake inhibitors (SSRIs)Antidepressants, selective serotonin reuptake inhibitors (SSRIs): Lee et al. conducted a study to assess the in vitro and in vivo effects of grapefruit juice on sertraline metabolism (60). The in vitro assay involved analysis of sertraline metabolism by CYP3A4 using CYP3A4-expressed human beta-lymphoblast microsomes. An in vitro study demonstrated that grapefruit juice can inhibit the metabolism of sertraline in a dose-dependent manner. The results of the in vivo study appeared to be consistent with the in vitro findings, in that mean (? SD) serum sertraline trough levels increased significantly from 13.7 ? 4.9mcg/L before to 20.2 ? 4.4mcg/L (p=0.047) after administration of grapefruit juice. AntifungalsAntifungals: Grapefruit may reduce the effectiveness of antifungal agents such as itraconazole possibly by presystemic intestinal metabolism via CYP3A4. Concomitant grapefruit juice was found to impair itraconazole absorption in a study of 11 volunteers (65). Administration with grapefruit juice resulted in a 43% decrease in the mean itraconazole AUC (0-48) (2,507ng.hour/mL vs. 1,434ng.hour/mL, p=0.046) and a 47% decrease in the mean hydroxy-itraconazole AUC(0-72) (7,264ng. hour/mL vs. 3,880ng.hour/mL, p=0.025); mean itraconazole tmax was also increased (5.5 vs. 4 hours). However, another report found no effect from coadministration of grapefruit juice on any pharmacokinetic parameter of itraconazole (66). AntihelminthicsAntihelminthics: Based on a human study, grapefruit may increase side effects associated with anthelmintics, especially praziquantel (41). The biotransformation of praziquantel appeared to be mediated mainlyby CYP3A4, and the increasein the bioavailability of praziquantel in this study suggestedthat it may be metabolized in the small intestine. AntihistaminesAntihistamines: Grapefruit may increase the bioavailability and side effects associated with antihistaminic herb or supplements. Grapefruit juice has been shown to increase absorption and plasma concentrations of terfenadine (67; 68; 69). Antimalarial herbs and supplementsAntimalarial herbs and supplements: Grapefruit juice has been shown to increase Cmax and AUC of antimalarial agents such as artemether and halofantrine (84; 86; 87). Halofantrine is metabolized into N-debutyl-halofantrine by CYP450 3A4. In a randomized crossover study, grapefruit juice increased halofantrine bioavailability and halofantrine-induced QT interval prolongation. Compared with water, grapefruit juice increased halofantrine AUC and peak plasma concentration by 2.8-fold ? 1.5-fold (p<0.0001) and 3.2-fold ? 1.3-fold (p<0.0001), respectively (84). Grapefruit juice significantly (p=0.001) increased Cmax of artemether more than two-fold from 42ng/mL to 107ng/mL. The tmax with grapefruit juice was 2.1 hours. The AUC almost doubled with grapefruit juice from 177ng.hour/mL to 336ng.hour/mL (p=0.003). The elimination half-life remained unchanged (1.0 hours vs. 1.3 hours). No signs of bradycardia or QTc prolongation were observed with coadministration of artemether and grapefruit juice (86). Results suggest that CYP3A4 in the gut wall is one of the metabolizing enzymes of artemether (86; 87).Grapefruit juice has been found to have no effect on quinine pharmacokinetics (9). AntineoplasticsAntineoplastics: Grapefruit may reduce the effectiveness of antineoplastic herbs or supplements. Grapefruit has been shown to decrease the absorption and plasma concentrations of etoposide (88). AntioxidantsAntioxidants: Grapefruit has been found to have antioxidant properties determine by oxygen radical scavenging property (172). AntiparasiticsAntiparasitics: Grapefruit may increase side effects associated with use of the antiparasitic agent artemether.AntipsychoticsAntipsychotics: Antipsychotic drugs such as clozapine and haloperidol have not been shown to be altered by grapefruit ingestion in human studies (90; 91; 92; 93). AnxiolyticsAnxiolytics: Grapefruit may increase the side effects associated with anxiolytics(42; 43; 44; 45; 46; 47; 48; 49; 50). Caffeine containing herbsCaffeine containing herbs: Clinical studies show that the ingestion of grapefruit juice should not cause any pharmacokinetic or pharmacodynamic interaction when coadministered with caffeine (103; 104; 105). Cardiac glycosidesCardiac glycosides: Clinical studies show that grapefruit juice increased the digoxin Cmax, but had no effect on AUC and half-life when compared with water (150; 151). Inhibition of intestinal P-glycoprotein does not appear to play an important role in drug interactions involving grapefruit juice and digoxin (150; 151). Cardiovascular herbs and supplementsCardiovascular herbs and supplements: Grapefruit is likely to increase the adverse effects associated with heart and blood pressure agents.Cytochrome P450 metabolized herbs and supplementsCytochrome P450 metabolized herbs and supplements: Preliminary evidence suggests that grapefruit juice may inhibit cytochrome P450 1A2 (30), cytochrome P450 2C9 (99; 30), or cytochrome P450 2C19 (30). Currently, these interactions have not been reported in humans. Grapefruit juice can inhibit CYP3A4 metabolism of drugs, causing increased drug levels and potentially increasing the risk of adverse effects (75; 64; 94; 141; 142; 31; 143; 144; 32; 33; 12; 34; 145; 146; 147; 148; 127; 53; 99; 131). DigitalisDigitalis: In theory, grapefruit juice may increase concentrations of digitalis (foxglove), although clinical significance is unknown.Green teaGreen tea: Based on anecdote, concomitant use of grapefruit and green tea may increase caffeine levels leading to an increased risk of cardiovascular and central nervous system stimulatory effects, along with other caffeine-related adverse effects due to caffeine in green tea. However, clinical studies show that the ingestion of grapefruit juice should not cause any pharmacokinetic or pharmacodynamic interaction when coadministered with caffeine (103; 104; 105). HypoglycemicsHypoglycemics: Grapefruit and grapefruit juice may raise blood glucose and theoretically may alter the effects of hypoglycemic agents.ImmunosuppressantsImmunosuppressants: Based on animal and human studies, grapefruit may increase absorption and plasma concentrations of immunosuppressants; however, the mechanism of action is unclear (132; 133; 134; 157; 159; 135; 10; 136; 137; 138; 53; 140; 158). Grapefruit may increase side effects associated with immunosuppressants. Increased levels of cyclosporine, methylprednisolone, and tacrolimus have been reported when taken with grapefruit (132; 133; 134; 157; 135; 10; 136; 137; 138; 158; 140). LicoriceLicorice: Grapefruit may interfere with the body's conversion of cortisol to cortisone. If both licorice and grapefruit are taken together, the risk of high blood pressure and other side effects may be increased (28). Neurologic herbs and supplementsNeurologic herbs and supplements: Grapefruit may interact with neurologic agents. For instance, grapefruit may increase the side effects associated with anxiolytics, such as benzodiazepines (42; 43; 44; 45; 46; 47; 48; 49; 50). Grapefruit may inhibit the metabolism of antidepressants (60; 61) and increase the side effects associated with tricyclic antidepressants (61). Peppermint oilPeppermint oil: Grapefruit may also interact with menthol or peppermint oil, possibly increasing effects.P-glycoprotein modulatorsP-glycoprotein modulators: Inhibition of P-glycoprotein activity by other compounds in grapefruit juice may be responsible for interactions and may interfere with P-glycoprotein regulated drugs (134; 74). Phytoestrogens, phytoprogestinsPhytoestrogens, phytoprogestins: Grapefruit may increase the bioavailability and side effects associated with estrogen (153; 154; 155). In one randomized crossover trial, grapefruit juice increased the ethinylestradiol Cmax significantly to 137% (p=0.0088) and increased the AUC(0-8) to 128% (p=0.0186) (155). Grapefruit juice has demonstrated the ability to alter the metabolic degradation of estrogens and increase the bioavailable amounts of 17beta-estradiol and its metabolite estrone in ovariectomized women (154). The most likely mechanism of action of the flavonoids of grapefruit juice on 17 beta-estradiol metabolism is the inhibition of the CYP450 3A4 enzyme, which catalyzes the reversible hydroxylation of 17 beta-estradiol into estrone and further into estriol (154). PotassiumPotassium: In theory, grapefruit may lower potassium levels in the blood.PsoralensPsoralens: Theoretically, grapefruit may interact with psoralens.Red yeast riceRed yeast rice: HMG-CoA reductase inhibitors are known to interact with grapefruit (74). Grapefruit may increase the Cmax and AUC of these agents (75; 76; 78; 79; 77; 80; 81; 12; 34; 82; 53; 83). Grapefruit juice may increase serum concentrations of lovastatin, a constituent of red yeast, probably by preventing CYP3A4-mediated first-pass metabolism in the small intestine (79). Vitamin CVitamin C: Grapefruit has been shown to increase plasma vitamin C levels (173). Grapefruit/Food/Drink Interactions:
Citrus soda (e.g. Sun Drop?, Fresca?)Citrus soda (e.g. Sun Drop?, Fresca?): Results from one randomized controlled study do not support a clinically relevant grapefruit juice-like interaction between oral cyclosporine and citrus sodas; however, an effect should not be ruled out (139). Red wineRed wine: Red wine in combination with grapefruit juice appears to have an additive inhibitory effect on CYP3A4, theoretically increasing the risk for interactions with other drugs (16). In contrast, white wine does not appreciably inhibit CYP3A4 activity. Tonic waterTonic water: Grapefruit's inhibitory effect on cytochrome P450 isoenzymes may interfere with the metabolism of quinine in tonic water. Grapefruit in combination with tonic water containing quinine should be avoided in people with cardiac rhythm disorders, such as long QT syndrome, which may worsen with quinine (15). Grapefruit/Lab Interactions:
Blood glucoseBlood glucose: Grapefruit and grapefruit juice may raise blood glucose.Coagulation panelCoagulation panel: Grapefruit juice decreased the urinary excretion of 7-hydroxycoumarin after oral administration of 10mg coumarin for up to eight hours (58). However, ingestion of grapefruit juice prepared from frozen concentrate did not change PTs or INRs in 10 patients treated with warfarin (174). CortisolCortisol: In vivo study has found that the dietary flavonoids in grapefruit juice may inhibit the enzyme 11?-hydroxysteroid dehydrogenase, which oxidizes cortisol to inactive cortisone, in a concentration dependent manner (27). Drug assaysDrug assays: Grapefruit juice decreases metabolism and increases plasma concentrations and test results of praziquantel (41), clomipramine (175; 61), artemether and halofantrine (84; 86; 87), amiodarone (51), amlodipine (39), diltiazem (112), felodipine (109; 113; 111; 108; 107; 114; 116; 124; 125; 126), nifedipine (107; 117; 119; 115; 129; 126; 13), nimodipine (121), verapamil (31; 118; 123), buspirone (102), midazolam and triazolam (42; 43; 44; 45; 46; 47; 48; 49; 50), diazepam (176), carbamazepine (59), dextromethorphan (149), cyclosporine (137; 177; 140), methylprednisolone (158), tacrolimus (157), digoxin (150; 151), erythromycin (33), clarithromycin (55), sildenafil (32; 160), atorvastatin (76; 12), lovastatin (79), simvastatin (77; 80; 81; 34; 83), 17-beta-estradiol (154), ethinyl-estradiol (154), methadone (165; 166), cisapride (168; 167; 169), amprenavir (40), saquinavir (95; 96), terfenadine (68; 69), quinidine (54), scopolamine (171), and theophylline (163). HematocritHematocrit: Research suggests that grapefruit may lower hematocrit count in people with an elevated hematocrit (36). Conversely, in people with a low hematocrit, it may increase hematocrit. The effect appears to be the same with one-half or a whole grapefruit daily. The grapefruit constituent naringin may be responsible for this effect. Serum lipid levelsSerum lipid levels: A 16-week double-blind, crossover study evaluating 27 patients with hypercholesterolemia at risk for coronary heart disease found that grapefruit pectin ingestion decreased plasma cholesterol level by 7.6%, LDL cholesterol by 10.8%, and LDL/HDL ratio by 9.8% (19). Serum potassium levelSerum potassium level: In vivo study has found that the dietary flavonoids in grapefruit juice may inhibit the enzyme 11?-hydroxysteroid dehydrogenase, which oxidizes cortisol to inactive cortisone, in a concentration dependent manner (28). High doses were observed to cause an apparent mineralocorticoid effect and theoretically, some individuals might increase their potassium clearance if they drink large amounts of grapefruit juice.