Grapefruit Juice and Drug Interactions

It was reported in 1991 that a single glass of grapefruit juice caused a twofold to threefold increase in the plasma concentration of felodipine, a calcium channel blocker, after oral intake of a 5-mg tablet, but a similar amount of orange juice showed no effect (98). Subsequent investigations demonstrated that pharmocokinetics of approximately 40 other drugs are also affected by intake of grapefruit juice (99). The main mechanism for enhanced bioavailability of drugs after intake of grapefruit juice is the inhibition of CYP3A4 in the small intestine. Grapefruit juice causes significant increases in the bioavailability of drugs after oral dosing but does not alter pharmacokinetic parameters of the same drug after intravenous administration. Therefore, it appears that grapefruit juice inhibits intestinal CYP3A4 but has no significant effect on liver CYP3A4 (100,101). Multiple drug-resistant (MDR) transporters play an important role in the disposition of many drugs. P-glycoprotein is a major MDR transporter that decreases the fraction of drug absorbed by carrying the drug back to the intestinal lumen from enterocytes. Although few studies showed activation of P-glycoprotein by grapefruit juice, most studies reported significant inhibition of P-glycoprotein by components of grapefruit juice (101,102). Furanocoumarins found in the grapefruit juice are probably responsible for interactions between grapefruit juice and drugs. The major furanocoumarin present in grapefruit juice is bergamottin which showed time-and concentration-dependent inactivation of cytochrome P 450 enzymes in vitro (103). Moreover metabolite of bergamottin (6',7' dihydrobergamottin) and a number of other furanocoumarin derivatives may also be involved in inhibiting CYP3A4 and CYP1B1 (104). Flavonoids such as naringin and naringenin may also play a role. Concentrations of such compounds also vary significantly between different sources of grapefruit juice. De Casto et al. (105) reported that concentrations of naringin may vary from 174 to 1492 ^mol/L among various grapefruit juices whereas concentrations of bergamottin varied from 1.0 to 36.6 ^mol/L. Therefore, the magnitude of grapefruit juice-drug interactions may also be variable. Paine et al. (106) reported that furanocoumarin-free grapefruit juice showed no interaction with felodipine, thus establishing that furanocoumarins are responsible for interactions between felodipine and grapefruit juice.

Time of ingestion of grapefruit juice also affects interaction between grapefruit juice and drugs. In most cases, ingestion of a single glass (~250ml) of regular strength grapefruit juice is enough to produce the effect of increased bioavailability of drugs. Lundahl et al. (107) observed no further change in pharmacokinetics of felodipine following 14 days of daily intake of grapefruit juice compared to the effects observed after the first glass. There is no need to take grapefruit juice along with a drug in order to observe the interaction. The bioavailability of lovastatin has been reported to double even when the drug was taken 12 h after intake of grapefruit juice (108). However, an interval of more than 24 h usually prevents a clinically significant interaction between a drug and grapefruit juice (109).

The oral formulation of cyclosporine (Sandimmun) has a variable absorption. The development of cyclosporine microemulsion (Sandimmun Neoral) resulted in increased bioavailability. Bistrup et al. (110) using eight stable renal transplant recipients demonstrated that grapefruit juice increased median AUC of cyclosporine (following oral administration of Sandimmun Neoral) by 38% whereas no change was observed in maximum cyclosporine concentration in blood or half-life of cyclosporine. Furono-coumarins containing drinks such as Sundrop Citrus Soda (registered trademark used under license of Dr Pepper/Seven Up Inc, 2002) may also produce grapefruit juice like effect with cyclosporine. A 32-year-old lung transplant recipient showed a trough cyclosporine concentration of 358 ng/mL 2 weeks after being discharged from the hospital. On the next four visits spanning 24 days, elevated cyclosporine concentrations were observed in two occasions. These values of 676 and 761 ng/mL were substantially higher that two other cyclosporine concentration of 319 and 374 ng/mL during the same time period. Furthermore, there was no change in dosage of cyclosporine. The higher cyclosporine concentrations correlated with consumption of Sundrop Citrus Soda during breakfast by the patient, which contains furocoumarin (111). Delayed effect of grapefruit juice on pharmacokinetcs and pharmacodynamics of tracrolimus has been reported in a living donor liver transplant recipient. The patient demonstrated a considerable increase in trough blood concentration of tacrolimus after concomitant ingestion of grapefruit juice (250 ml) four times a day for 3 days. The trough blood concentrations were not affected during or immediately after repeated intake of grapefruit juice. However, almost 1 week after final ingestion of grapefruit juice, the trough tacrolimus concentration increased to 47.4 ng/mL from a preingestion tacrolimus concentration of 4.7 ng/mL (112).

Interactions between grapefruit juice and antiepileptic drugs have been reported. In a randomized crossover study involving 10 patients with epilepsy, grapefruit juice (300 ml) increased the trough concentration of carbamzaepine (4.51 ^g/mL in the control group vs. 6.28 ^g/mL in the grapefruit juice group). The steady-state carbamazepine concentrations were also significantly increased in patients who ingested grapefruit juice and carbamazpine in comparison to the control group (113). In contrast, grapefruit juice has no effect on the pharmacokinetics and bioavailability of another anticonvulsant drug phenytoin (114).

Saquinavir, a HIV protease inhibitor, has poor bioavailability due to extensive metabolism in the intestine initiated by CYP3A4. Oral bioavailability of saquinavir increased by a factor of 2 following ingestion of 400 ml of grapefruit juice without affecting clearance. This effect was absent when the drug was delivered by intravenous administration (115). In contrast, grapefruit juice slightly decreased maximum serum concentration of another HIV protease inhibitor amprenavir (7.11 ng/mL in the presence of grapefruit juice vs. 9.10 ng/mL in the control), but the difference was not clinically significant (116). Grapefruit juice did not have any significant effect on bioavailability and pharmacokinetics of indinavir (117).

Interactions between grapefruit juice and various calcium channel antagonists have been extensively studied in the past. The most striking effect was observed with felodipine where increases up to 430% in maximum serum concentration and increases up to 300% in AUC had been observed in the presence of grapefruit juice. A further decrease in diastolic blood pressure was also observed when felodipinen was taken with grapefruit juice as well as adverse effects such as increased heart rate and orthostatic hypotension (98). Similar interactions with grapefruit juice were also observed with nisoldipine and nicardipine. Increased bioavailability of nitrendipine (100% increases), pranidipine (73% increases) and nimodipine (50% increases) were also observed in the presence of grapefruit juice (100,101). A significant increase in bioavailability of verapamil in the presence of grapefruit juice has also been reported (118).

Grapefruit juice increases bioavailability of several benzodiazepines including diazepam, triazolam and midazolam but has no effect on alprazolam even after repeated intake (101). Ozdemir et al. (119) reported a threefold increases in AUC of diazepam due to intake of grapefruit juice. Grapefruit juice also interacts with cholesterol lowering drugs. Simvastatin, a substrate for CYP3A4, is extensively metabolized during first pass. Grapefruit juice (200 ml once a day for 3 days) increased the AUC (0-24 h) of simvastatin by 3.6-fold and simvastatin acid by 3.3-fold. The peak concentrations were also increased significantly, and only one glass of grapefruit juice taken daily is capable of producing such effects (120). On the other hand, when subjects ingested double strength grapefruit juice three times a day (200 ml) for 3 days, the peak serum concentrations and the AUC were increased by 12.0-fold and 13.5-fold respectively compared to the control. When simvastatin was taken 24 h after ingestion of grapefruit juice, the effect of grapefruit juice on AUC of simvastatin was only 10% of the effect observed during concomitant intake of simvastatin with grapefruit juice (109). Grapefruit juice increased the AUC (0-24 h) of atorvastatin acid by 83% whereas the AUC of pitavastatin was increased by only 13% (121).

Digoxin is a substrate of P-glycoprotein. In a study involving 12 healthy volunteers, grapefruit juice had no significant effect on maximum plasma drug concentration of digoxin or the AUC (0-48 h) (122). However in another study involving 12 volunteers, administration of cisapride with grapefruit juice (250 ml) increased the AUC of cisapride by 151% and maximum plasma concentration by 168% (123). Grapefruit juice has modest effect in increasing the AUC (0-48 h) of itraconazole by 17% and reduces oral clearance of itraconazole by 14% (124).

Although most reports indicate increased bioavailability of drugs in the presence of grapefruit juice or no clinically significant interaction, Dresser et al. reported significant reduction in bioavailability of fexofenadine, a non-sedating antihistamine. This drug does not undergo any significant intestinal or hepatic metabolism. Recent developments indicate that the family of drug uptake transporters known as organic anion transporting polypeptides (OATPs) play an important role in disposition of certain drugs. In the small intestine, OATPs facilitate absorption of certain medications, and inhibition of this transport system may cause reduced bioavailability. Grapefruit juice (300 or 1200 ml) produced lower mean maximum plasma concentration and AUC of fexofenadine compared to when the drug was taken with the same volume of water. The mean maximum plasma concentration of fexofenadine was 436 ng/mL when the drug was taken with 300 ml of water compared to the mean maximum plasma concentration of 233 ng/mL when the medication was administered with 300 ml of grapefruit juice. The reduction of maximum plasma concentration was more striking in the presence of 1200 ml of grapefruit juice. Similar reductions were also observed in AUC of fexofenadine. Because fexofenadine is a zwitter ion, it has high solubility in aqueous medium over a wide pH range, and it is unlikely that acidic pH of grapefruit juice could reduce the solubility significantly. Therefore, authors postulated that ingredients of grapefruit juice have prolonged inhibitory effects on inherent activity of intestinal OATP-A activity, thus causing a clinically significant effect of reduced bioavailability of fexofenadine (125). Common interactions between drugs and fruit juices are given in table 3.

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