Grapefruit Juice

Brand Names:

Clinical Names: Grapefruit Juice

Summary

Grapefruit Juice

overview of interactions:
• food potentially affecting drug pharmacokinetics, toxicity and performance: Cytochrome P450 Inhibition

• food affecting drug performance: Corticosteroids, including Prednisone

• food affecting drug performance and toxicity: Cyclosporine

• food affecting drug performance: Lovastatin

• food affecting drug performance: Pravastatin

• food affecting drug toxicity: Terfenadine (Seldane®)

• food affecting drug performance and toxicity: Verapamil





Interactions

food potentially affecting drug pharmacokinetics, toxicity and performance: Cytochrome P450 Inhibition

• mechanism: Ongoing research has now identified a number of compounds that are responsible for the net effect of grapefruit juice upon the down-regulation of Cytochrome P450 isoenzymes. The in vivo importance of different grapefruit juice compounds in CYP inhibition is unknown. However, it appears that the CYP3A4 enzymes are primarily inhibited by furanocoumarin compounds, rather than flavonoids, such as naringin, as was initially suspected, and that some components of CYP inhibition remain unidentified. In vitro studies have further identified that grapefruit juice also acts on the P-glycoprotein (efflux pump) of duodenal enterocytes, as well as on intestinal CYP 3A4, and it has been suggested that some of the high variation in individual responses to grapefruit juice ingestion on drug availability is due to P-glycoprotein inhibition.
(Edwards DJ, et al. Drug Metabol Disp 1996; 24: 1287-1290; Fukuda K, et al. Biol Pharm Bull 1997; 20: 560-564; Fukuda K, et al. Pharmacogenetics 1997;7:391-396; Lown K, et al. J Clin Invest 1997; 99: 2545-2553.)

• nutritional concern: Detailed research on the effect of grapefruit juice on individual drug bioavailability is needed. In the meantime, it would generally be prudent to maintain any situation of regular drug therapy and concomitant grapefruit juice consumption if there are or have been no adverse effects. There appears to be no need to remove grapefruit juice from the diet if it has been regularly consumed with no ill effects or other indications of adverse interaction. On the other hand, it would be advisable to avoid adding grapefruit juice to the diet after stabilization on drug therapy. These cautions are especially important with calcium channel blockers (see below). The exception, due to the possible severity of interaction effects, is the antihistamine drug terfenadine (Seldane®). Grapefruit juice consumption during terfenadine use should be avoided under any circumstances.
(Bailey DG, et al. Br J Clin Pharmacol. 1998 Aug;46(2):101-110; Spence JD. Clin Pharmacol Ther 1997; 61: 395-400.)


food affecting drug performance: Corticosteroids, including Prednisone

• interactions: Naringenin, quercetin and kaempferol, which may be found in glycoside form in natural compounds such as grapefruit, are potent inhibitors of cytochrome P-450 metabolism. Inhibition of cytochrome P-450 activity in the blood contributes to sustaining blood levels of corticosteroids. Moderate amounts of flavonoids, such as quercetin, can also be found in apples, onions and tea, with smaller amounts available in leafy green vegetables and beans.
(Schubert W, et al. Eur J Drug Metab Pharmacokinet 1995 Jul-Sep;20(3):219-224.)

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) oxidizes cortisol to inactive cortisone. Its absence or inhibition increases cortisol levels at the mineralocorticoid receptor, causing mineralocorticoid effects. This mineralocorticoid action of cortisol causes a drop in serum potassium and an increase in serum sodium concentration, together with a metabolic alkalosis, which can lead to water retention, weight gain, and an increased risk of hypertension. Dietary flavonoids, such as found in grapefruit juice, can inhibit this enzyme and at high doses may cause an apparent mineralocorticoid effect.
(Lee YS, et al. Clin Pharmacol Ther 1996 Jan;59(1):62-71.)

food affecting drug performance and toxicity: Cyclosporine

• mechanism: Grapefruit juice increases blood concentrations of some dihydropyridine calcium-channel blockers, which are metabolized by the P450 enzymes that also metabolize cyclosporine. Thus concurrent administration of grapefruit juice with cyclosporine will delay the absorption of the cyclosporine and increase the drug exposure of cyclosporine without changing peak concentration.

• research: Ioannides-Demos et al conducted a randomized crossover study with nine patients comparing the effects of grapefruit juice and water on steady state blood concentrations of cyclosporine and metabolites in patients with autoimmune diseases. They found that over a period of ten days, the relatively large amount of grapefruit juice involved, five ounces twice daily, produced a significant increases in predose cyclosporine concentrations and total metabolite concentrations when taken at the same time as the cyclosporine. One patient complained of abdominal pain and nausea as well as significant neurological side effects including tremor and lightheadedness.
(Ioannides-Demos LL, et al. J Rheumatol 1997;24:49-54.)

• potential nutritional synergy and risk: Lower doses of cyclosporine could potentially be used to achieve the desired levels in the body when administered in conjunction with a typical 8 oz. serving of grapefruit juice. Thus grapefruit juice might be used to provide a non-toxic and inexpensive alternative to drugs that are used to reduce cyclosporin dose. However, at this time clinical use of such a therapeutic approach would be wholly speculative. In the meantime physicians and pharmacists might caution patients taking cyclosporine against drinking grapefruit juice while taking cyclosporine to prevent any alterations in the effects of the medicine. No such effect has been reported with consumption of grapefruits as a food.
(Yee GC, et al. Lancet 1995 Apr 15;345(8955):955-956; Min DI, et al. Transplantation 1996 Jul 15;62(1):123-125.)

food affecting drug performance: Lovastatin

• mechanism: Grapefruit juice increases the bioavailability of many drugs by preventing CYP3A4-mediated first-pass metabolism in the small intestine.
(Bailey DG, et al. Br J Clin Pharmacol. 1998 Aug;46(2):101-110.)

• research: Kantola et al conducted an open, randomized, two-phase crossover study with ten subjects looking at the interaction between lovastatin and grapefruit juice. They concluded that, compared to placebo, grapefruit juice can greatly increase serum concentrations of lovastatin and its active metabolite, lovastatin acid.
(Kantola T, et al. Clin Pharmacol Ther 1998;Mar;63(4):397-402.)

• nutritional concerns and possible synergy: Individuals taking lovastatin should avoid drinking grapefruit juice, especially within two hours of taking lovastatin. Any regular consumption of grapefruit juice should be discussed with the prescribing physician so they are aware of the potential interaction. Kantola et al recommended that the dose of lovastatin be reduced accordingly in individuals who continued to consume grapefruit juice. While the consumption of grapefruit juice with lovastatin might theoretically enable the use of lower doses of the drug to achieve the same therapeutic effect, no conclusive research on this potential synergistic approach has been published. Any such attempt at combining lovastatin and grapefruit therapeutically would require close monitoring by the prescribing physician. Therefore anyone taking lovastatin should avoid changing their dose of the medication based on their consumption of grapefruit juice without first consulting their prescribing physician.

food affecting drug performance: Pravastatin

• mechanism: Grapefruit juice increases the bioavailability of many drugs by preventing CYP3A4-mediated first-pass metabolism in the small intestine.
(Bailey DG, et al. Br J Clin Pharmacol. 1998 Aug;46(2):101-110.)

• research: Kantola et al conducted an open, randomized, two-phase crossover study with ten subjects looking at the interaction between grapefruit juice and lovastatin, a statin drug similar to pravastatin. They concluded that, compared to placebo, grapefruit juice can greatly increase serum concentrations of lovastatin and its active metabolite, lovastatin acid. No research has yet been published looking at the potential interaction between lovastatin and grapefruit juice. While the research with lovastatin raises concerns the four commonly used HMG-CoA reductase inhibitors, lovastatin, simvastatin, pravastatin, and fluvastatin, have different pharmacokinetic characteristics.
(Kantola T, et al. Clin Pharmacol Ther 1998;Mar;63(4):397-402.)

• nutritional concerns and possible synergy: Even though no direct research has emerged to demonstrate that a high risk prevails, individuals taking pravastatin would be prudent to avoid drinking grapefruit juice, especially within two hours of taking the drug. While the consumption of grapefruit juice with lovastatin might theoretically enable the use of lower doses of the drug to achieve the same therapeutic effect, no conclusive research on this potential synergistic approach has been published. Given the doubly speculative nature of this potential interaction, anyone taking any of the HMG-CoA reductase inhibitor drugs should avoid changing their dose of the medication based on their consumption of grapefruit juice without first consulting their prescribing physician. While Kantola et al recommended that the dose of lovastatin be reduced accordingly in individuals who continued to consume grapefruit juice, no one has published research or clinical recommendations to this effect with regard to pravastatin.

food affecting drug toxicity: Terfenadine (Seldane®)

• report: A fatality attributed to Seldane (terfenadine) and grapefruit juice interaction leading to cardiac failure on exertion was reported by Spence. The post-mortem levels of terfenadine and its metabolites were elevated (not normally detectable). the patient had a history of regular grapefruit juice consumption and used terfenadine twice daily for allergic rhinitis.

• research: Benton analyzed the arryhthmogenic effects of coadministration of terfenadine and grapefruit juice in a cross-over study and found significant prolongation of QT interval and quantifiable levels of terfenadine in 100% of the subjects.
(Benton RE, et al. Clin Pharmacol Ther 1996, 59: 383-388; Rau SE, et al. Clin Pharmacol Ther 1997 Apr;61(4):401-409; Spence JD. Clin Pharmacol Ther 1997;61:395-400.)

• nutritional concern: Individuals using terfenadine or astemazole should avoid consuming grapefruit juice. Other non-sedating anti-histamines are available which do not appear to interact with grapefruit juice, e.g., loratidine (Claritin®).

food affecting drug performance and toxicity: Verapamil

• mechanism: While not as pronounced as with many other medications, the consumption of grapefruit juice at the same time as verapamil may measurably increase levels of drug in the blood.
(Bailey DG, et al. Br J Clin Pharmacol 1998 Aug;46(2):101-110.)

• research: In a two-day study involving ten hypertensive patients on chronic verapamil treatment Zaidenstein found no significant effect on the pharmacokinetics of verapamil as a result of a single administration of grapefruit juice in conjunction with short-acting verapamil.
(Zaidenstein R, et al. Eur J Clin Pharmacol 1998 Jun;54(4):337-340.)

• nutritional concerns and possible synergy: The clinical significance of the interaction between verapamil and grapefruit juice has yet to demonstrated in clinical studies. Some physicians and researchers have discussed a possible role for grapefruit juice as a drug-sparing agent which might facilitate a reduction in the prescribed dose of the drug. The clinical application of this possible synergistic interaction seems premature at this time given the lack of data on the effectiveness and side effects of such a combined treatment approach. Individuals taking verapamil should heed the warning against drinking grapefruit juice unless they have consulted their prescribing physician and are under direct supervision and monitoring.
(Fuhr U. Drug Saf 1998 Apr;18(4):251-272; Holt GA. 1998, 274-275.)


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Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.



References

Bailey DG, et al. Grapefruit juice-drug interactions. Br J Clin Pharmacol. 1998 Aug;46(2):101-110. (Review)
The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6',7'- dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans.

Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice and drugs - How significant is the interaction? Clin Pharmacokinet. 1994;26(2):91-98.

Benton RE, Honig PK, Zamani K et al. Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram. Clin Pharmacol Ther 1996, 59: 383-8.
Objectives: To establish whether the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine are affected by concomitant administration of grapefruit juice and to determine whether any effect of grapefruit juice is dependent on the timing of administration in relation to the dose of terfenadine. Methods. Twelve healthy volunteers were studied in a prospective randomized trial. The primary end points were QT prolongation on the surface electrocardiogram and the pharmacokinetic parameters: area under the concentration-time curve (AUC), maximum concentration, and time to maximum concentration of terfenadine and its acid metabolite terfenadine carboxylate. All subjects received 60 mg terfenadine twice a day with 240 mL water for 7 days. They were then randomized to drink 240 mL of double-strength grapefruit juice simultaneously with terfenadine (simultaneous group) for an additional 7 days or to drink the same dose of grapefruit juice 2 hours after terfenadine for 7 days (delayed group). Twelve timed electrocardiograms and plasma terfenadine and metabolite levels were measured on days 7 and 14. Results. None of the 12 subjects had quantifiable levels of terfenadine when the drug was administered with water. All six subjects who took terfenadine and drank grapefruit juice simultaneously had quantifiable terfenadine levels. Only two of six who drank grapefruit juice 2 hours after terfenadine had quantifiable levels. The AUC of the acid metabolite increased 55% (p < 0.05) in the simultaneous group and 22% (p = NS) in the delayed group. The mean QT interval increased from 420 to 434 msec (p < 0.05) in the simultaneous group and decreased from 408 to 407 msec (p = NS) in the delayed group. Conclusions: Administration of grapefruit juice concomitantly with terfenadine may lead to an increase in systemic terfenadine bioavailability and result in increases in QT interval. The clinical significance of an increase in QT interval of this magnitude is unclear.

Edwards DJ, Bellvue FH, Woster PM. Identification of 6',7'-Dihydroxybergamottin, a cytochrome p450 inhibitor in grapefruit juice. Drug Metabol Disp 1996; 24: 1287-90.

Emilia G, Longo G, Bertesi M, Gandini G, Ferrara L, Valenti C. Clinical interaction between grapefruit juice and cyclosporine: is there any interest for the hematologists? Blood 1998 Jan 1;91(1):362-363. (Letter)

Fukuda K, Ohta F, Yamazoe Y. Grapefruit component interacting with rat and human p450 CYP3A: possible involvement of non-flavonoid components in drug interaction. Biol Pharm Bull 1997; 20:
560-4.

Fukuda K, Ohta T, Oshima Y et al. Specific CYP3A4 inhibitors in grapefruit juice: furocoumarin dimers as components of drug interaction. Pharmacogenetics 1997; 7: 391-6.

Lown K, Bailey DG, Fontana RJ et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 1997; 99: 2545-53.

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998.

Kantola T, Kivisto KT, Neuvonen PJ. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1998;Mar;63(4):397-402.
Abstract: BACKGROUND: Grapefruit juice increases the bioavailability of several drugs known to be metabolized by CYP3A4. We wanted to investigate a possible interaction of grapefruit juice with lovastatin, a cholesterol-lowering agent that is partially metabolized by CY P3A4. METHODS: An open, randomized, two-phase crossover study with an interval of 2 weeks between the phases was carried out. Ten healthy volunteers took either 200 ml double-strength grapefruit juice or water orally three times a day for 2 days. On day 3, each subject ingested 80 mg lovastatin with either 200 ml grapefruit juice or water, and an additional dose of 200 ml was ingested 1/2 and 1 1/2 hours after lovastatin intake. Serum concentrations of lovastatin and lovastatin acid were measured up to 12 hours. RESULTS: Grapefruit juice greatly increased the serum concentrations of both lovastatin and lovastatin acid. The mean peak serum concentration (Cmax) of lovastatin was increased about 12-fold (range, 5.2-fold to 19.7-fold; p < 0.001) and the area under the concentration-time curve [AUC(0-12)] was increased 15-fold (range, 5.7-fold to 26.3-fold; p < 0.001) by grapefruit juice. The mean Cmax and AUC(0-12) of lovastatin acid were increased about fourfold (range, 1.8-fold to 11.5-fold; p < 0.001) and fivefold (range, 2.4-fold to 23.3-fold; p < 0.001) by grapefruit juice, respectively. The half-lives of lovastatin and lovastatin acid remained unchanged. CONCLUSIONS: Grapefruit juice can greatly increase serum concentrations of lovastatin and its active metabolite, lovastatin acid, probably by preventing CYP3A4-mediated first-pass metabolism in the small intestine. The concomitant use of grapefruit juice with lovastatin and simvastatin should be avoided, or the dose of these 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors should be reduced accordingly.

Lee YS, Lorenzo BJ, Koufis T, Reidenberg MM. Grapefruit juice and its flavonoids inhibit 11 beta-hydroxysteroid dehydrogenase. Clin Pharmacol Ther 1996 Jan;59(1):62-71.
Abstract: INTRODUCTION: The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) oxidizes cortisol to inactive cortisone. Its congenital absence or inhibition by licorice increases cortisol levels at the mineralocorticoid receptor, causing mineralocorticoid effects. We tested the hypothesis that flavonoids found in grapefruit juice inhibit this enzyme in vitro and that grapefruit juice itself inhibits it in vivo. METHODS: Microsomes from guinea pig kidney cortex were incubated with cortisol and nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP) and different flavonoids and the oxidation to cortisone measured with use of HPLC analysis. In addition, healthy human volunteers drank grapefruit juice, and the ratio of cortisone to cortisol in their urine was measured by HPLC and used as an index of endogenous enzyme activity. RESULTS: Both forms of 11 beta-OHSD requiring either NAD or NADP were inhibited in a concentration-dependent manner by the flavonoids in grapefruit juice. Normal men who drank grapefruit juice had a fall in their urinary cortisone/cortisol ratio, suggesting in vivo inhibition of the enzyme. CONCLUSION: Dietary flavonoids can inhibit this enzyme and, at high doses, may cause an apparent mineralocorticoid effect.

Merkel U, Sigusch H, Hoffman A. Grapefruit juice inhibits 7-hydroxylation of coumarin in healthy volunteers. Eur J Clin Pharmacol. 1994;46(2):175-177.
Abstract: The effect of grapefruit juice on the urinary excretion of 7-hydroxycoumarin after oral administration of 10 mg coumarin, as an index of cytochrome P450 dependent coumarin metabolism, has been investigated in an open, randomised cross over study in 13 healthy volunteers (7 female, 6 male). The percentage of 7-hydroxycoumarin found in urine was significantly decreased up to 8 h after simultaneous intake of 300 ml grapefruit juice. If the same volume of juice was swallowed 30 min prior to the administration of coumarin, 7-hydroxycoumarin excretion was delayed by up to 6 h. MRTexcr. of coumarin was 70% extended by coadministration of grapefruit juice. It appears that grapefruit flavonoids inhibit cytochrome P450 2A dependent metabolic pathways. The mechanism of cytochrome P450 inhibition by these flavonoids is still poorly understood.

Min DI, Ku YM, Perry PJ, Ukah FO, Ashton K, Martin MF, Hunsicker LG. Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients. Transplantation 1996 Jul 15;62(1):123-125.
Abstract: This study investigated the effect of grapefruit juice on cyclosporine A (CsA) bioavailability in 10 renal transplant patients. Under CsA steady state conditions, patients were randomly administered their usual dose of CsA with either 8 ounces of grapefruit juice or 8 ounces of water. Using a crossover design, a 12-hr pharmacokinetic study was then conducted. Grapefruit juice increased the area under the concentration versus time curve (4218+/-1497 ng x hr/ml [grapefruit juice] vs. 3415+/-1288 ng x hr/ml [water], P=0.029) and 12-hr trough (244+/-214 ng x ml [grapefruit juice] vs. 132+/-56 ng x ml [water], P=0.09), but it did not change peak concentration (734+/-290 ng x ml [grapefruit juice] vs. 708+/-305 ng x ml [water], P=0.76). In addition, grapefruit juice delayed the time to peak concentration compared with water (5.4+/-3.0 hr [grapefruit juice] vs. 2.8+/-0.8 hr [water], P=0.025). These data suggest that concurrent administration of grapefruit juice with CsA will delay the absorption of CsA and increase the drug exposure of CsA without changing peak concentration.

Pronsky Z. Powers and Moore's Food-Medications Interactions. Ninth Edition. Food-Medication Interactions. Pottstown, PA, 1991, 60.


Rau SE; Bend JR; Arnold MO; Tran LT; Spence JD; Bailey DG Clin Pharmacol Ther 1997 Apr;61(4):401-9.
Abstract: OBJECTIVE: To investigate the single dose-response effects of grapefruit juice on terfenadine disposition and electrocardiographic measurements. METHODS: Twelve healthy males received 250 ml water or regular- or double-strength grapefruit juice with 60 mg terfenadine in a randomized crossover trial. Plasma concentrations of the cardiotoxic agent terfenadine and the active antihistaminic metabolite terfenadine carboxylate were determined over 8 hours. The QTc interval was monitored. RESULTS: Terfenadine concentrations were measurable (> 1 ng/ml) in 27 (20%; p < 0.001) and 39 (30%; p < 0.001) samples from individuals treated with regular- and double-strength grapefruit juice, respectively, compared to only four (3%) samples with water. Terfenadine plasma peak drug concentration (Cmax) was also higher. Terfenadine carboxylate area under the plasma drug concentration-time curve (AUC), Cmax, and time to reach Cmax (tmax) were increased by both strengths of juice. However, terfenadine carboxylate apparent elimination half-life (t1/2) was not altered. The magnitude of the interaction of terfenadine carboxylate AUC and Cmax ranged severalfold and correlated among individuals for regular-strength (r2 = 0.87; p < 0.0001) and double-strength (r2 = 0.78; p < 0.0001) grapefruit juice. No differences in the pharmacokinetics of terfenadine and terfenadine carboxylate were observed between the two strengths of grapefruit juice. QTc interval was not altered. CONCLUSIONS: A normal amount of regular-strength grapefruit juice produced maximum single-dose effects on terfenadine and carboxylic acid metabolite pharmacokinetics. The mechanism likely involved reduced presystemic drug elimination by inhibition of more than one metabolic pathway. The extent of the interaction was not sufficient to produce electrocardiographic changes. However, the pharmacokinetic effects were highly variable among individuals. This study further enhances the awareness of the potential for a serious interaction between grapefruit juice and terfenadine.

Schubert W, Eriksson U, Edgar B, Cullberg G, Hedner T. Flavonoids in grapefruit juice inhibit the in vitro hepatic metabolism of 17 beta-estradiol. Eur J Drug Metab Pharmacokinet 1995 Jul-Sep;20(3):219-224.
Abstract: Naringenin, quercetin and kaempferol, which may be found in glycoside form in natural compounds such as grapefruit, are potent inhibitors of cytochrome P-450 metabolism. The influence of these flavonoids on the metabolism of 17 beta-estradiol was investigated in a microsome preparation from human liver. The flavonoids were added in concentrations of 10, 50, 100, 250 and 500 mumol/l to the microsome preparation. The metabolism of 17 beta-estradiol was concentration dependently inhibited by all the flavonoids tested. Addition of the flavonoids to the microsome preparation did not influence estrone formation, while a potent inhibition of estriol formation was observed. At the highest concentrations tested of the respective flavonoid, there was approximately 75-85% inhibition of estriol formation. However, naringenin was a less potent inhibitor of 17 beta-estradiol metabolism as compared to quercetin and kaempferol. The most likely mechanism of action of the flavonoids on 17 beta-estradiol metabolism is inhibition of the cytochrome P-450 IIIA4 enzyme, which catalyzes the reversible hydroxylation of 17 beta-estradiol into estrone and further into estriol. These hydroxylation processes represent the predominant steps of the hepatic metabolic conversion of endogenous as well as exogenous 17 beta-estradiol. This interaction would be expected to inhibit the first-pass metabolism of 17 beta-estradiol, and this has recently been demonstrated after oral administration of 17 beta-estradiol to women.

Spence JD. Drug interactions with grapefruit: whose responsibility is it to warn the public ? Clin Pharmacol Ther 1997; 61: 395-400.

Sullivan DM, Ford MA, Boyden TW. Grapefruit juice and the response to warfarin. Am J Health Syst Pharm. 1998 Aug 1;55(15):1581-1583.
Abstract: The effect if any of prepared frozen grapefruit juice on prothrombin times (PTs) in patients undergoing stabilized warfarin therapy was studied. Patients receiving low-intensity warfarin therapy (targeted International Normalized Ratio [INR], 2-3) who had two consecutive baseline PTs within 10% of each other were recruited. Patients who regularly consumed grapefruit juice or alcohol or who were taking drugs known to interact with grapefruit juice were excluded. A one-week supply of freshly prepared frozen grapefruit juice in individual 8-oz containers was given to all the subjects, who were told to drink the entire contents of on container three times a day for one week. PTs were measured and INRs calculated on the day before grapefruit juice ingestion began (day 0) and a days 2, 6, and 8. Ten men (mean age, 66 years) were enrolled; one withdrew because of diarrhea. Compliance in consuming the juice was reported to range from 85.7% to 100% among patients. There was no significant difference among PT or INR values over the course of the study in any of the nine subjects. Ingestion of grapefruit juice prepared from frozen concentrate did not change PTs in patients treated with warfarin.

Yee GC, Stanley DL, Pessa LJ, Dalla Costa T, Beltz SE, Ruiz J, Lowenthal DT. Effect of grapefruit juice on blood cyclosporin concentration. Lancet 1995 Apr 15;345(8955):955-956.
Abstract: Grapefruit juice increases blood concentrations of some dihydropyridine calcium-channel blockers, which are metabolised by the P450 enzymes that also metabolise cyclosporin. We evaluated, in a randomised cross-over study, the effect of grapefruit juice on blood cyclosporin concentrations in 14 healthy adults. Each subject was given oral cyclosporin 300 mg with 250 mL grapefruit juice, orange juice, or water. Area-under-the-curve (AUC) was significantly higher with grapefruit juice than with water or orange juice (means 7057, 4871, and 4932 ng h/mL, respectively; p < 0.0001). Thus grapefruit juice may provide a non-toxic and inexpensive alternative to drugs that are used to reduce cyclosporin dose.

Zaidenstein R, Dishi V, Gips M, Soback S, Cohen N, Weissgarten J, Blatt A, Golik A. The effect of grapefruit juice on the pharmacokinetics of orally administered verapamil. Eur J Clin Pharmacol 1998 Jun;54(4):337-340.
Abstract: OBJECTIVE: To investigate the effect of grapefruit juice (GJ) on the pharmacokinetics of orally administered verapamil in hypertensive patients. METHODS: Ten hypertensive patients on chronic verapamil treatment participated in a two-day study. On day 1 200 ml of water was given 1 hour before, and together with the morning verapamil dose; on the day 2, water was replaced by GJ in the same order. Serial blood samples were collected and the concentrations of verapamil and its main dealkylated metabolite (D-617) were determined by high-performance liquid chromatography (HPLC). The area under the concentration versus time curve of verapamil (AUCv) and its metabolite D-617 (AUCM) were calculated before and after GJ ingestion. The peak serum concentration (Cmax) and the time until its appearance (tmax) were also determined. RESULTS: GJ did not affect Cmax, tmax, AUCv or AUVm. The AUCv/AUCm ratio (AUCR) was slightly, but significantly, increased after GJ (1.67 vs 1.92). CONCLUSIONS: A single administration of GJ with short-acting verapamil has no significant effect on the pharmacokinetics, of verapamil.