Summary of studied drugs
Most medications investigated for an interaction with grapefruit juice are substrates for CYP3A4 (Table 1). The most extensively studied are the dihydropyridine calcium channel antagonists. In addition to felodipine [5, 8, 12, 14–18], these include nisoldipine , nimodipine , nicardipine , nitrendipine [22, 23], nifedipine [12, 24–26], and amlodipine [27, 28], which have similar pathways of metabolism , but vary markedly in absolute oral bioavailability dependent upon extent of presystemic drug elimination .
Innate oral drug bioavailability and mean relative drug AUC and Cmax
with grapefruit juice compared with control (%) among studies.
Based on the previous discussion, it would be expected that a dihydropyridine with low inherent oral bioavailability would have a greater magnitude of the interaction with grapefruit juice than with a dihydropyridine with normally high oral bioavailability. Nisoldipine  and amlodipine  are examples of dihydropyridines with very low and very high innate oral bioavailability, respectively. Mean (range) drug Cmax for nisoldipine was 406% (107%–836%)  and for amlodipine was 115% (79%–165%)  with grapefruit juice compared with water. Thus, nisoldipine did have a much greater fold increase of plasma drug concentrations compared with amlodipine. Furthermore, interindividual variability of the interaction was larger for nisoldipine which highlights the unpredictability of the interaction among individuals for dihydropyridines with low oral bioavailability.
All dihydropyridines, apart from nifedipine, have a chiral centre with activity primarily residing with a particular enantiomer . The relevance of an interaction with grapefruit juice then depends mostly on the magnitude of increase of the more active enantiomer. For nitrendipine, the S-enantiomer possesses the activity [30, 31]. Grapefruit juice produced proportional enhancement of both enantiomers indicating that the increase in plasma total nitrendipine concentration was predictive of the pharmacodynamic extent of interaction . For nicardipine, the S-enantiomer has one-third the activity of the R-enantiomer . Grapefruit juice augmented S-nicardipine AUC and Cmax by 1.5-and 1.2-fold more than R-nicardipine demonstrating that the effect on plasma total nicardipine concentration may slightly overestimate associated clinical consequences . The S-enantiomer of non-dihydropyridine calcium channel antagonist, verapamil, has at least 10 times the dromotropic activity compared with the R-enantiomer . Grapefruit juice produced less than a doubling of mean plasma total verapamil AUC and Cmax . However, first degree heart block (PR interval >240 ms) was observed in only subjects (4 of 24) who received verapamil with grapefruit juice. Although inter-subject variation of the interaction was not reported, grapefruit juice may preferentially augment S-verapamil and thus, the increase in plasma total verapamil concentrations would underestimate the importance of the interaction.
The non-sedating antihistamine, terfenadine, undergoes nearly complete presystemic elimination mediated by CYP3A4 [35, 36] and is often not detected in plasma. One of the primary metabolites, terfenadine carboxylate, accounts for the activity . Terfenadine, like quinidine, is a potent blocker of myocyte delayed rectifier potassium current whereas terfenadine carboxylate is devoid of this effect [37–39]. Plasma terfenadine concentrations can be measured with overdose, liver disease or inhibition of CYP3A4 metabolism by concomitant administration of ketoconazole, erythromycin or itraconazole and are associated with prolongation of the QTc interval and development of a serious ventricular tachyarrhythmia, torsades de pointes [40–52]. Approximately 125 deaths linked to terfenadine have been reported . Controlled clinical investigations have shown that grapefruit juice augmented plasma terfenadine concentrations [54–57]. A small increase in the QTc interval was demonstrated [54, 55]. The magnitude of the interaction was similar to that produced by itraconazole or erythromycin . A fatality has been attributed to terfenadine toxicity after consuming the drug with grapefruit juice . Since there appears to be little benefit from taking grapefruit juice with terfenadine and there is the potential for a serious adverse interaction, regardless of the frequency of occurrence, it seems wise to advise against grapefruit juice consumption during therapy with terfenadine.
Midazolam and triazolam are two ultra-short acting benzodiazepine hypnotics with high presystemic drug metabolism. For midazolam, a substantial portion of presystemic metabolism appears to occur in the small bowel [59, 60] and the major primary metabolite, 1′-hydroxymidazolam, is generated by CYP3A4 . Grapefruit juice increased mean midazolam AUC and Cmax by an estimated 41% selective decrease of prehepatic midazolam metabolism . Psychometric tests showed greater patient impairment when oral midazolam was administered with grapefruit juice compared with water. Similarly, grapefruit juice augmented triazolam AUC and Cmax to produce enhanced drowsiness .
Cyclosporin is the cornerstone of immunosuppression therapy following transplantation. Plasma cyclosporin concentrations must be maintained within a narrow range to achieve adequate immunosuppression without nephrotoxicity. However, cyclosporin possesses low and variable oral bioavailability. Although this has been attributed to poor drug solubility and diffusion characteristics, more recent work has supported presystemic cyclosporin metabolism as a factor . In two studies of healthy volunteers, grapefruit juice produced mean oral cyclosporin AUCs which were 162% and 143% of that with water [65, 66]. Orange juice did not augment cyclosporin AUC . Several studies were conducted in medically stable renal transplant patients [67–71]. Grapefruit juice was given with the patient's usual oral dose of cyclosporin to achieve steady state. The effect of grapefruit juice on cyclosporin pharmacokinetics varied among studies. Plasma cyclosporin AUC [68, 70, 71] and trough concentration [67, 70], which is commonly used during therapeutic drug monitoring, were augmented in some investigations. The largest mean interaction was a cyclosporin AUC and trough concentration with grapefruit juice that were 134% and 177%, respectively, of that compared with water . There was more than a tripling in plasma trough cyclosporin concentration in at least one patient which undoubtedly is clinically important . Because cyclosporin is very expensive, administration with grapefruit juice has been suggested as a technique to decrease drug costs . However, the magnitude of the effect is variable among patients and the constancy of the interaction with repeat dosing has not been documented. Thus, concurrent administration of grapefruit juice cannot presently be recommended as a therapeutic strategy for such patients .
The anti-AIDS drug, saquinavir, belongs to a new class of agents known as protease inhibitors. Its very low bioavailability is in part due to presystemic metabolism by CYP3A4. A glass of regular-strength grapefruit juice augmented saquinavir AUC to 150% of that with water in HIV-negative volunteers . Double-strength grapefruit juice enhanced saquinavir AUC to 220%. Since saquinavir has a wide therapeutic window, concomitant administration of grapefruit juice has been suggested as a strategy to increase saquinavir bioavailability. Although the magnitude of the interaction may be variable among patients, there appears to be only the potential for enhanced therapeutic benefit.
Grapefruit juice did not interact with a number of other medications. These include prednisone , acenocoumarol , quinidine  and theophylline . This is not unexpected since these drugs already have high or almost complete oral bioavailability. Prednisone and theophylline are also not substrates for CYP3A4. However, grapefruit juice did prolong the systemic elimination half-life of caffeine, a probe for CYP1A2 activity, and theophylline is metabolized by CYP1A2 . This discrepancy for theophylline may be resolved by a recent report suggesting that grapefruit juice decreased caffeine elimination by inhibition of flavin-containing monooxygenase, a P450 independent system which does not appear to metabolize theophylline . Other medications not showing an interaction with grapefruit juice include propafenone , diltiazem , ethinyloestradiol  and 17β-oestradiol . Although they undergo presystemic metabolism, it appears that a substantial portion is by pathways not mediated by CYP3A4.
Drugs predicted to interact with grapefruit juice
The HMG-CoA reductase inhibitor, lovastatin, has been reported to produce a serious adverse skeletal muscle effect, rhabdomyolysis, when administered with drugs that inhibit CYP3A4 including itraconazole , erythromycin  and cyclosporin . Lovastatin is a prodrug which normally undergoes extensive presystemic elimination . Less than 5% of lovastatin is hydrolyzed to the pharmacologically active metabolite, lovastatin acid, with the majority biotransformed by other primary routes mediated by CYP3A4 . Lovastatin and active metabolite AUCs were increased more than twenty-fold when administered with itraconazole suggesting the adverse effect has a pharmacokinetic basis . Rhabdomyolysis has also been reported with simvastatin [88, 89] and pravastatin [90, 91]. Thus, a clinically important interaction may occur between grapefruit juice and lovastatin and possibly other HMG-CoA reductase inhibitors.
Prolonged QT interval, torsade de pointes and fatal arrhythmia have been reported with the gastrointestinal prokinetic agent, cisapride . Adverse events occurred in conditions where plasma cisapride concentrations were elevated, particularly with concomitant administration of medications that inhibit CYP3A4. Cisapride normally undergoes presystemic metabolism by CYP3A4 resulting in a 40–50% absolute oral bioavailability . Torsade de pointes has also been observed with the non-sedating antihistamine, astemizole, when administered with ketoconazole . Astemizole has high presystemic elimination by three major metabolic routes to produce an estimated 3% oral bioavailability . Unless medical condition warrants their use, it might be prudent to avoid the combination of grapefruit juice with cisapride or astemizole.