In a randomized crossover fashion, 10 healthy volunteers (5 male, 5 female) received alfentanil 23 mcg/kg orally following either no pretreatment, or grapefruit juice pretreatment consisting of 240 mL SSGJ at bedtime the night before the study period, and 90 mL DSGJ 1 hour prior to oral alfentanil ingestion. A minimum 2 week washout period was employed between sessions.

Maximum serum concentration (Cmax) following oral alfentanil were increased 38% and time to this peak concentration (Tmax) was increased 33% while total alfentanil exposure (AUC) was increased 64%. Alfentanil half-life was essentially unchanged.

Alfentanil is normally poorly absorbed (mean 42% oral absorption) when given orally. Alfentanil availability was increased to a mean 62% when alfentanil was given orally with grapefruit juice pre-treatment. A noticeable increase in pupillary miosis (decrease in pupil size) and miosis duration was observed in the GJ group, compared to the control group. All subjects tolerated the study well, with no nausea or requirement for oxygen in the GJ-pretreated group. The authors did not comment on the clinical significance of the change in alfentanil blood levels and AUC.¹²⁵

amiodarone (Cordarone^®)

Amiodarone is a class III antiarrhythmic drug. It has the potential to cause serious adverse effects in patients receiving it on a long-term basis.  Nevertheless, it remains a commonly used medication, for the treatment of arrhythmias in patients resistant or intolerant to other medications.  Amiodarone has an extremely long elimination half-life (approximately 50 days).

Eleven healthy male volunteers were given a 17 mg/kg dose (approx. 1200 mg - a reasonable loading dose) with either 300 mL water or 3x300 mL glasses of single-strength GJ (at 0h, 3h, 9h).  The study was non-randomized due to the long half-life of amiodarone, and the long (6 month) washout period between study phases.  All patients had their amiodarone kinetics and ECG monitored after water intake, followed in 6 months by the GJ kinetic determinations.  GJ completely inhibited production of N-desethylamiodarone (N-DEA) (the major metabolite of amiodarone) in all subjects, and increased the AUC by 50%, and the peak concentration by 84% on average.  N-DEA is an active metabolite and is produced mainly by CYP 3A4. 

ECG changes were noted in both the water and GJ phase. In the water phase, the PR interval and QTc interval increased by +17.9%+/- 6.6% and +11.3%+/-8.0% respectively.  The increases were lower in the GJ group: PR increased by +10.2%+/-8.8% and QTc increased by +3.3%+/-4.5%. For both periods RR intervals and QRS durations were not statistically altered, and systolic arterial pressure decreased slightly.

Although the extent of ECG changes observed was not of concern, the authors state that these changes could be important in patients suffering cardiomyopathy and/or from conduction or rhythmic disorders.  Inhibition of N-DEA production could decrease the antiarrhythmic action of amiodarone, but this could also conversely decrease the arrhythmogenic effects linked to QT prolongation. Further investigation is warranted.⁶⁵

budesonide (Entocort^® capsules)

After extensive intake of grapefruit juice (observed in male subjects taking in 600 mL of concentrated grapefruit juice per day for 4 days), the systemic exposure for oral budesonide increased approximately 2-fold. As with other drugs primarily being metabolized through CYP3A, regular ingestion of grapefruit or its juice, should be avoided in connection with budesonide administration.³⁴

carvedilol (Coreg^®)

Unpublished data shows that co-administration of GJ with carvedilol leads to a 16% increase in bioavailability.  The clinical significance of this interaction is unknown.³⁴

celiprolol (Selectol^®)

In a randomized crossover design, 12 healthy volunteers (9 male, 3 female) aged 21-23 years received celiprolol 100 mg after intake of either water or 200 mL SSGJ x 6 doses over 2 days before and 2 days after celiprolol administration.

No significant changes in heart rate, blood pressure or any adverse effects were noted.

When  compared to water, GJ significantly decreased the total drug exposure (AUC) of celiprolol by 85%, decreased peak level (Cmax) by 95% and prolonged half-life by 85% and time to peak concentration (Tmax) by 50%.

The authors are known to use higher amounts of GJ for multiple doses compared with other research teams. Theories were offered for the decline in celiprolol absorption, including p-glycoprotein effects, Organic Anion Transporting Peptide (OATP) effects, as well as physicochemical factors: celiprolol is a weak base with pH of 9.5. GJ has a pH of approx. 3.3. This may have lowered the pH in the intestinal lumen, and increased the amount of ionized celiprolol. Since the ionized form of celiprolol is less lipid soluble, it may not be as well absorbed.

The authors concluded that this interaction is probably clinically relevant, due to the greatly reduced absorption of celiprolol.¹⁰⁸ Similar reductions in absorption of celiprolol were observed in a study conducted by the same authors using orange juice instead of grapefruit juice.¹⁰⁹

cisapride (Prepulsid^®, Propuslid^®) 

Cisapride is metabolized by cytochrome p450 3A4 (CYP3A4), the main enzyme implicated in grapefruit juice-drug interactions.   Cisapride is contraindicated to be administered with erythromycin, clarithromycin, ketoconazole and fluconazole, which all have inhibitory effects at CYP3A4, similar to GJ.  In addition, high blood levels of cisapride may be associated with cardiac arrhythmias, including torsades des pointes, QTc interval prolongation and ventricular arrhythmias.  The recommended maximum dose of 40 mg/day should not be exceeded, and it is prudent to avoid co-administration with GJ, given the potentially serious outcomes that have resulted due to interactions between cisapride and CYP3A4 inhibiting drugs. 

Recently, documentation of this interaction has been published.⁴⁴  Thirteen healthy volunteers were given either 240 mL water or single-strength GJ with a single 10mg dose of cisapride in a randomized crossover study.   Significant effects included a 39% increase in AUC when cisapride was administered with GJ. The peak concentration was increased 34% and the time to reach peak concentration was increased 37%, from 1.26 hours to 1.72 hours.  Considerable inter-individual variation in GJ effect was noted.  No changes in heart rate, blood pressure or QTc interval were observed.  Mild adverse effects including headache and gastrointestinal disturbances were reported, but were more frequent after ingestion of cisapride with water. The authors concluded that although no adverse effects were seen in this single dose study, it would be prudent to advise patients not to take cisapride with GJ or any grapefruit products.  In individuals stabilized on large cisapride dosages, GJ could result in high peak cisapride concentrations.  A potential adverse effect for cisapride is development of fatal cardiac arrhythmias, including torsades des pointes. 

10 healthy male volunteers were given either 200 mL water or double-strength GJ three times daily for 2 days, followed by 10 mg of cisapride with either 200 mL of GJ or water, in a randomized crossover fashion. An additional 200 mL of fluid was ingested 30 and 90 minutes after cisapride administration.  Cisapride AUC was increased by an average of 144% and peak concentration was increased by an average of 81%.  The time to peak blood level was prolonged from 1.5 to 2.5 hours, and the half-life was prolonged from 6.8 hours in the subjects receiving water to 8.4 hours in the GJ group.  No ECG changes in QTc interval were noted in any patient.  The authors concluded that concomitant use of high amounts of GJ and cisapride should be avoided, at least in patients with risk factors for cardiac arrhythmia.⁶⁰ 

A follow-up study of 10 healthy volunteers were given a single dose of cisapride 10 mg after consuming 200 mL of either double-strength GJ or water three times daily for 2 days prior to cisapride dosing. AUC and Cmax levels of the (-) and (+) enantiomers of cisapride were elevated after GJ use, and the proportion of pharmacokinetic changes brought about by GJ was similar for both enantiomers, suggesting non-stereoselective interaction. No significant difference in mean QTc intervals was found between the water and GJ groups.¹⁰⁰ 

Cisapride was removed from the Canadian market as of August 2000, due to the potential for serious cardiac adverse effects and interactions with drugs which can inhibit CYP 3A4 metabolism of cisapride (e.g. erythromycin, ketoconazole). This is a similar interaction as with GJ.  Studies of this interaction conducted at steady-state blood levels are needed.

colchicine

A single case report of colchicine interacting with GJ exists. An 8-year old patient with familial Mediterranean fever was hospitalized with vomiting, abdominal pain and fever. The child had been receiving colchicine 2mg daily for approximately 10 months. 2 months prior to admission, the child began ingesting approximately 1 liter of GJ daily. The patient developed acute CHF, shock and pancytopenia and required ICU admission, G-CSF (filgrastim) therapy, transfusion and antibiotic therapy. Recovery was complicated by temporary severe alopecia, atony and weakness.  No blood levels of colchicine were drawn. The authors suggested that the child developed acute colchicine intoxication due to inhibition of CYP 3A4 metabolism by GJ. Colchicine is an older drug, and its metabolic pathways have not been clearly defined, including whether or not CYP 3A4 is responsible for its metabolism.⁷²

dextromethorphan (Robitussin DM^®, Balminil DM^®, many others)

Eleven healthy volunteers (6 male, 5 female) received 30mg dextromethorphan daily for 5 days with either 200 mL single-strength GJ (study day 2), 200 mL seville orange juice (SOJ) (study day 4), or water (study day 1, 3, 5) in a linear, non-crossover fashion. Immediately, the non-crossover design raises a concern, since the effect of GJ on the enzymes is known to persist for 72 hours or more. A 3 -day washout was given after study day 2, and at least 7-days passed between study day 2 and 4. 

Blood levels were not collected in this study. Urine point assays, and 8-hour total urine concentrations were used to determine dextromethorphan availability in a complicated series of analyses, based partially on animal data, and some assumptions.

The fraction of the administered dose of dextromethorphan that escaped first pass metabolism were found to increase significantly and similarly when GJ or SOJ were taken with dextromethorphan on study days 2 and 4, although lack of an adequate washout period after GJ intake on day 2 was provided, the administration of SOJ with dextromethorphan produced an identical effect on the dextromethorphan pharmacokinetic profile as was observed with GJ. Two volunteers experienced drowsiness, but were found to be CYP 2D6 "poor metabolizers" (the alternate metabolic pathway for dextromethorphan and its metabolites).  It also appears that both GJ and SOJ affected p-glycoprotein transport protein activity.⁹⁴

digoxin (Lanoxin^®)

In a randomized crossover fashion, 12 healthy volunteers (7 male, 5 female) were given a single oral dose of digoxin (a p-glycoprotein substrate that is not metabolized by CYP 3A4) 0.5 mg with either water or 250 mL of SSGJ 30 minutes prior to the dose, and 3.5, 7.5 and 11.5 hours after the dose. A two-week washout between study periods was employed.

Compared to the water group, mean peak blood concentrations (Cmax) rose 21%, time to peak level (Tmax) rose 8%, and total drug exposure at 48 hours (AUC48) rose 9%. None of these changes were statistically significant.  AUC at 4 and 24 hours also rose 9% and this was considered statistically significant. 

2 subjects experienced asymptomatic first-degree atrioventricular block on the EKG 90 minutes after digoxin ingestion. PR interval prolongation spontaneously returned to normal over the study period in both subjects. Both of these subjects had a 50% digoxin Cmax increase during the grapefruit period (peak levels were 2.4 ng/mL and 2.8 ng/mL respectively). It was genetically determined that both subjects had high P-glycoprotein expression.

The authors consider GJ a weak inhibitor of P-glycoprotein, since studies with other known P-glycoprotein inhibitors show larger increases in digoxin AUC. They concluded that the study did not support the role of GJ as an important P-glycoprotein inhibitor, and that the modest increases in digoxin concentrations observed did not require any recommendations to alter digoxin dosing or titration when taken with GJ.¹¹⁴

In a similar study, 7 healthy volunteers (4 male, 3 female) received a single oral dose of digoxin 1 mg with with either water or GJ in a randomized crossover design. A washout of two weeks between study periods was employed.

During the GJ phase, 240 mL of SSGJ was consumed 3 times daily for 5 days prior to digoxin administration, and 6 days after digoxin administration, in an attempt to maximize the effect on p-glycoprotein.

Compared to water, administration of digoxin with GJ showed peak blood levels (Cmax) decreased by a mean of 16%, total drug exposure (AUC) increased 3%, Time to peak concentration (Tmax) increased 25% and half-life was essentially unchanged (decreased by 3%). None of these changes were determined to be statistically significant, although significant interindividual variability was observed.

The authors concluded that when results are taken with the previous study, GJ ingestion does not have a significant effect on intestinal P-glycoprotein activity, and that P-glycoprotein inhibition does not play an important role in grapefruit interactions.¹¹⁵

ethinyl estradiol/17-B estradiol

Concurrent administration of ethinyl estradiol with GJ (n=13) increased the Cmax by 37% and the AUC by 28%.¹⁹  These effects are likely due to decreased pre-systemic elimination of ethinyl estradiol.    17-B estradiol increased bioavailability was noted especially in the first 24 hours (n=8).²⁴  The clinical significance of these findings is unknown at this time.

etoposide (Vepesid^®)

In a randomized crossover study, 6 patients with lung cancer took the oral anti-cancer drug etoposide with either water or 100 mL of SSGJ (a lower than usual amount). AUC was decreased by a mean of 26% in the GJ group. Cmax differences were not reported for this study.  Significant inter-patient variability was observed. Etoposide is demethylated in the liver by CYP 3A4, but its absorption has also been demonstrated to be at least in part dependent on p-glycoprotein, and GJ may have caused an alteration of intestinal p-glycoprotein mediated transport.⁹³

fentanyl (Actiq^®)

Approximately 25% of a dose of oral transmucosal fentanyl undergoes transmucosal absorption, and a significant portion (75%) of the dose is swallowed, absorbed intestinally, and subject to first-pass metabolism (66% of the swallowed dose). Total overall bioavailability from this dosage form is approximately 50%. 

In a randomized crossover fashion, 12 healthy volunteers (6 male, 6 female) aged 20-32 years received a single dose of 10 mcg/kg by oral transmucosal fentanyl lozenge with either no pretreatment or 250 mL SSGJ on the evening prior to the study day, and 100 mL DSGJ 1 hour prior to fentanyl administration. A washout period of 7-14 days was employed between study dates.

Compared to the control group, with GJ intake peak fentanyl blood levels (Cmax) were increased by 11% (non-significant), while time to peak level and total drug exposure (AUC) were unchanged. Peak concentration of the major metabolite norfentanyl (Cmax) was decreased 29%, with total drug exposure essentially unchanged. 

Time to peak miosis effect (pinpoint pupils) was increased by 37% with GJ. No subjects in the GJ group experienced respiratory depression, versus 1 subject in the control group. One subject in both the control group and the GJ required treatment for nausea/vomiting. GJ did not have a significant effect on the absorption of oral transmucosal fentanyl.¹²²

losartan (Cozaar^®, Hyzaar^®)

In a randomized crossover design, 9 healthy volunteers (7 male, 2 female) of Ashkenazi Jewish origin, aged 30-48 years, received losartan 50 mg with either 200 mL water or GJ of unspecified strength.

None of the volunteers experienced adverse effects. Total drug exposure (AUC) to losartan was increased 17%, peak losartan levels (Cmax) increased 2%, time to peak concentration (Tmax) increased 46%, and half-life decreased by 11%. 

The E3174 metabolite is important in losartan activity since it is more potent than losartan, and has a considerably longer half-life (5.6 hours, compared to 1.9 hours for losartan).

The active metabolite of losartan, E3174 had total exposure (AUC) decreased by 21%, peak levels (Cmax) decreased 21%, time to peak concentration (Tmax) decreased 11% and half-life increased 14%.

The AUC ratio of losartan to its E3174 metabolite increased significantly by 41% when losartan was given with GJ. E3174 is thought to be produced by CYP 2C9 and CYP 3A4 metabolism, and this study confirms that CYP 3A4 is involved in losartan metabolism.

The authors concluded that grapefruit administration had minimal effect on losartan and E3174 pharmacokinetics.⁸⁸

methadone (Methadose^®, Dolophine^®)

In a crossover fashion, 10 opioid-dependent patients undergoing methadone treatment received either water or 200 mL SSGJ 30 minutes prior to their usual dose of methadone daily for 4 days. The study session took place on the fifth day, when the patients also drank an additional 200 mL water or SSGJ, followed by 2 more 200 mL portions of water or SSGJ. All intake of methadone was supervised, and absence of illicit drug use was verified by urine testing prior to study commencement, and on the day of testing.

Two patients were excluded from the analysis for protocol violations. No patient experienced any sign of methadone overdosage during the study. A significant decrease in adverse effects was noted in the GJ group.

Total methadone exposure (AUC) and peak levels (Cmax) for both the R and S enantiomers of methadone were all increased by a mean of 17%. A 15% increase in apparent half-life of combined R and S enantiomers was noted, but  GJ was not associated with any change in the intensity of withdrawal symptoms or time that methadone "held" the patients.

The authors concluded that GJ led to a modest increase in total drug exposure (AUC) and peak levels (Cmax).¹¹² 

In a very complicated study protocol, 12 healthy subjects (8 male, 4 female) aged 18-39 years and free of opioid-dependence, received in a crossover fashion, 4.5 mg methadone intravenously, and 10 mg radio-labelled methadone orally following either no pretreatment, or 250 mL SSGJ on the day prior to the study, with 100 mL DSGJ on the study day prior to drug administration. The study sessions had a washout period of not less than 2 weeks. 

GJ had essentially no effect on IV methadone administration (total drug exposure (AUC) increased 2%, peak levels (Cmax) decreased 12% and half-life increased 3%.)

For oral methadone administration, Cmax was increased 38%, with AUC increased 19%. Time to peak concentration increased 5%, and half-life was increased 3 %. These increases are within the range of the increase seen with the study done in opioid-dependent individuals.¹¹³

methylprednisolone (Medrol^®)    

In a crossover design, 10 healthy volunteers were given either 200 mL water or double-strength (DS) GJ three times daily for 2 days. On day 3, subjects were given a single 16mg dose of oral methylprednisolone with 200 mL water or DSGJ. A repeated ingestion of 200 mL water or DSGJ occurred at 0.5h and 1.5h after the methylprednisolone dose.  The AUC of methylprednisolone was increased 75% by GJ.  Cmax was increased by 27%, and time to peak levels (Tmax) was prolonged from 2h to 3h with GJ.  Half-life was significantly prolonged by 35% (from 2.1h +/- 0.5h to 2.8h +/- 0.3h) in the GJ group. The authors suggest that since half-life was prolonged, systemic (i.e. liver) metabolism of methylprednisolone was also inhibited by GJ.  The clinical significance of the interaction was deemed to be small, but in sensitive subjects, high doses of GJ may enhance the effects of oral methylprednisolone.  Note: although not directly studied, injectable methylprednisolone is unlikely to be affected by GJ.⁷⁴

omeprazole (Losec^®, Prilosec^®) 

Omeprazole is a proton-pump inhibitor which acts as a powerful suppressant of secretion of stomach acid. To determine the effect of grapefruit juice on omeprazole metabolism in vivo, a randomized crossover trial was done in 13 healthy volunteers with a single 20 mg dose of omeprazole and either 300 mL of water or 300 mL of single-strength GJ.  The AUC of omeprazole was increased by 11% when given with GJ compared to the water group, while peak concentration was unchanged between the two groups.  The degree of this interaction is not significant, as far as use of omeprazole in patients, but it does provide some clues as to which enzyme systems are affected.  AUC ratio of 5-hydroxyomprazole to omeprazole were decreased 20% in the GJ group, while the AUC ratio of omeprazole-sulphone to omeprazole was decreased 33%.  Omeprazole-sulphone is mainly formed by CYP 3A4, while formation of 5-hydroxyomeprazole is dependent on CYP 2C19 activity. CYP 2C19 is more liver specific, while formation of omeprazole-sulphone occurs mainly in intestinal CYP 3A4.   Furthermore, plasma half-life of 5-hydroxyomeprazole which is mainly mediated by hepatic CYP 3A4 was not significantly different between the two phases of the study.⁶⁹

quinidine

One study of 12 healthy volunteers reported both decreased AUC and peak plasma concentrations of 3-hydroxyquinidine (the major metabolite of quinidine) and an increase in time to reach peak concentrations and effect of quinidine, due to possible inhibition of gut wall metabolism during drug absorption.  Even though there was reduced conversion of quinidine to its active metabolite with delayed absorption of quinidine, the AUC of quinidine remained unchanged.²⁰  Quinidine has a high oral bioavailability and therefore a small change in bioavailability may not be as significant as it would be with agents with a low bioavailability.  The effects on QT interval were not significant, though this study was conducted in healthy patients without pre-existing arrhythmias.

6 healthy males were given a single 200 mL dose of quinidine with either nothing or 250 mL of single-strength GJ. The elimination half-life of quinidine was increased by 19% from 7.0h to 8.3h.  There was no change in the peak concentration of quinidine. AUC of quinidine was not reported for this study.  Total clearance of quinidine was reduced by 15%. ECG measurements were not performed in this study.  GJ administration was concluded to cause minor but significant changes in the metabolism of quinidine.⁶⁶

quinine

Quinine is widely used for the treatment of malaria. In North America, it is more frequently used for prevention of nocturnal leg cramps in elderly patients.  Quinine is mainly metabolized by CYP3A4.  The effects of GJ on on the pharmacokinetics of quinine were studied.⁵⁴ Ten healthy subjects received either 200 mL orange juice, single-strength GJ or half-strength GJ twice daily for 5 days in a randomized crossover fashion.  On day 6 of the study, subjects were given a single oral dose of 600mg of quinine with the appropriate fluid. GJ intake did not significantly affect any pharmacokinetic parameters, including quinine Cmax, AUC, Tmax, and half-life. The pharmacokinetics of the 3-hydoxyquinine were slightly changed with GJ.  The authors concluded that it is not necessary to advise patients against ingesting GJ at the same time that they take quinine.

Somewhat contradicting this study is a case report of a 31 year old woman who was admitted with the cardiac arrhythmia torsade de pointes (QTc interval 580 msec). She was known to have asymptomatic long QT syndrome, and had been drinking large amounts of GJ and quinine-containing tonic water due to polydipsia secondary to diabetes and hyperglycemia.

The arrhythmia resolved after 48 hours of stopping intake of GJ and tonic water. QTc interval was 450 msec at this time.¹¹⁶

scopolamine (Hyoscine^®) 

Fourteen healthy volunteers (7 male, 7 female) received single oral 0.5 mg doses of the anticholinergic agent, scopolamine in a randomized crossover fashion with either 250mL water or fresh-squeezed, not from concentrate, single-strength GJ. Cmax was decreased 11%, while AUC was increased 35%, and time to peak level (Tmax) was extended from 23.5 minutes to 59.5 minutes (153% increase).  Subjects reported similar decreases in alertness from scopolamine in both the water and GJ groups. All women were taking oral contraceptives with standard doses of estrogen/progestin and were studied at the same time during their cycle, to minimize effects on pharmacokinetics. Females had comparably lower Cmax levels when administered intravenous scopolamine to calculate absolute bioavailability.⁸⁹

sildenafil (Viagra^®)

Sildenafil is a medication used for treatment of erectile dysfunction. Its metabolism is known to be mediated primarily via CYP 3A4. Twenty-four healthy male volunteers (average age 29) received sildenafil 50 mg in a randomized crossover fashion with either 250 mL of unknown-strength GJ or water given 1 hour prior to dosing, and concurrent with dosing. AUC was increased 23% and Cmax was decreased 4% with GJ. Time to peak concentration (Tmax) was prolonged from 45 to 67 minutes (50% increase). No major changes in heart rate or blood pressure were observed during the study periods. The magnitude of increase in AUC in this study is in the lower range of increases in AUC observed in other GJ-drug interaction studies.  The variable individual extent of interaction makes pharmacokinetics of sildenafil less predictable when taken with GJ. The authors recommend avoiding the combination, especially in patients susceptible to more pronounced hemodynamic responses.

The delay in reaching Tmax may be significant, since it is usually recommended to take sildenafil 1 hour prior to sexual activity, with the assumption that Cmax is reached at the time point of desired action. Occasionally, particular sildenafil users might be surprised by a delay in onset of drug action after drinking GJ.⁹¹