Juice and Cranberry Juice

Pomelo, closely related to grapefruit, interacts with cyclosporine. In a study involving 12 healthy male volunteers, 200 mg dose of cyclosporine was administered with 240 ml of pomelo juice. The average maximum concentration of cyclosporine in blood was 1494 ng/mL when cyclosporine was administered with pomelo juice compared to an average concentration of 1311 ng/mL when cyclosporine was administered along with water. However, intake of cyclosporine along with cranberry juice had no effect on bioavailability of cyclosporine. Authors concluded that pomelo juice increased bioavailability of cyclosporine possibly by inhibiting CYP3A4, P-glycoprotein activity or both (126). Pomelo juice also increases the blood level of tacrolimus. Egashira et al. reported a case where a 44-year-old male with a renal transplant showed therapeutic concentrations of tacrolimus 3 months after transplant. His tacrolimus concentration varied between 8 and 10 ng/mL, and in one occasion, he showed a blood tacrolimus concentration of 25.2 ng/mL. There was no change of tacrolimus dose. The patient consumed about 100 gm of pomelo grown in his garden. Pomelo contains furanocoumarins and was considered responsible for increased bioavailability of tacrolimus in this patient (127).

Components of pomegranate juice are potent inhibitors of CYP3A4. Hidaka et al. demonstrated that incubation of pomegranate juice (5% by vol) with human liver microsome resulted in 1.8% residual activity of CYP3A for converting carbamazepine

Table 3

Common Fruit Juiceā€”Drug Interactions

Fruit juice

Interacting drug

Comments

Grapefruit juice

Pomelo juice

Pomegranate juice Cranberry juice

Orange juice Seville orange juice

Felodipine

Nitrendipin Pranidipine Nimodipine Cyclosporine

Tacrolimus

Diazepam

Traizolam/midazolam

Carbamazepine

Saquinavir

Simvastatin

Atorvastatin

Pitavastatin

Fexofenadine

Digoxin

Cyclosporine

Tacrolimus

Carbamazepine

Warfarin

Pravastatin Simvastatin

Celiproolo Felodipine

A 430% increase in maximum plasma level of felodipine Bioavailability increased by 100% Bioavailability increased by 73% Bioavailability increased by 50% Increased blood level of cyclosporine

Increased of trough concentration delayed by 1 week Increased plasma concentration Increased plasma concentration Increased plasma concentration Increased plasma concentration AUC increased by 3.6-fold AUC increased by 83% AUC increased by only 13% Plasma level reduced from 436 ng/mL (300 ml of water) to 233 ng/mL (300 ml of grapefruit juice)

No clinically significant interaction

Increased concentration of cyclosporine Increased blood level of tacrolimus

Increased AUC of carbamazepine by 1.5-fold

INR >50 in a patient due to interaction of warfarin with cranberry juice. The patient died. Increased INR in two other patients

Increased AUC of pravastatin No clinically significant interaction

AUC reduced by 83%

AUC of felodipine increased by

AUC, area under the curve; INR, international normalization ratio.

to carbamazepine 10, 11-epoxide. The residual activity of CYP3A after 30-min incubation with pomegranate juice was 47.5% compared to 38.3% residual activity when treated with grapefruit juice. Moreover in comparison with water, the AUC of carbamazepine was approximately 1.5-fold higher with pomegranate juice (2 ml) that was orally given 1 h before oral administration of carbamazepine in rats (128).

Cranberry juice is a potent inhibitor of human and rat CYP3A, and oxidation of nifedipine can be decreased in vitro in the presence of cranberry juice. Moreover, in vivo experiments with rats demonstrated that AUC of nifedipine was 1.6-fold higher when 2 ml of cranberry juice was intradudenally introduced 30 min prior to the intraduodenal administration of nifedipine (30 mg/kg). These data suggest that cranberry juice inhibits the function of enteric CYP3A (129). Interaction between cranberry juice and warfarin has also been reported. After a chest infection, a man had a poor appetite and had nothing but cranberry juice for 2 weeks as well as his regular drugs (digoxin, phenytoin and warfarin). Six weeks after starting with cranberry juice, he was admitted in the hospital with an INR of over 50. He died of gastrointestinal and pericardial hemorrhage. Cranberry juice contains flavonoids that can inhibit cytochrome P 450, and warfarin is predominately metabolized by CYP2C19. Authors concluded that patients taking warfarin should not consume cranberry juice (130). Another case report indicated elevated INR in a patient on warfarin 2 weeks after the patient started drinking cranberry juice. Subsequent symptoms included postoperative bleeding problem (131).

Orange juice increased AUC (0-4 h) of pravastatin (a 3-hydroxy-3-methyl glutaryl CoA reductase inhibitor) in healthy volunteers when administered orally. Orange juice also increased AUC of pravastatin in rats when the drug was given orally but demonstrated no effect when pravastatin was administered intravenously. However, orange juice had no effect on bioavailability of simvastatin another 3-hydroxy-3-methyl glutaryl CoA reductase inhibitor (132). Orange juice also enhances aluminum absorption from antacid preparation. In a study involving 15 normal subjects when antacid "Aludrox" was taken with orange juice, there was an approximately 10-fold increase in 24 h urinary excretion of aluminum. However, milk had no effect on aluminum absorption (133). Several published reports also indicated reduced bioavailability of several drugs when taken orally along with orange juice. Kamath et al. reported that orange juice and apple juice significantly reduced oral bioavailability of fexofenadine in rats (31 and 22%, respectively). This may be related to inhibition of OATPs (134). It was discussed earlier that grapefruit juice also reduced oral bioavailability of fexofenadine (134). Orange juice substantially reduced the bioavailability of celiprolol, a ^-adrenergic receptor blocking agent used in the treatment of hypertension. In a study involving 10 healthy volunteers, orange juice (200 ml) reduced the mean peak plasma concentration of celiprolol by 89% (330.0 ng/mL in control and 35.5 ng/mL in subjects taking orange juice). The AUC was also reduced by 83% due to intake of orange juice. The authors concluded that this interaction is likely to have clinical importance (135). Another report indicated that orange juice reduced bioavailability of clofazimine (used in treatment of multidrug-resistant Mycobacterium tuberculosis and leprosy) in humans. Aluminum-based antacids also reduced bioavailability of clofazimine, whereas a fatty meal increased the bioavailability (136).

Sour orange also known as bitter or Seville orange is different from a sweet orange. Malhotra et al. reported that Seville orange juice increased AUC of felodipine by 76%, whereas grapefruit juice increased the AUC by 93%. The concentration of bergamottin and 6,7-dihydoxybergamottin were 5 and 36 ^mol/L in Seville orange juice, whereas concentrations of bergamottin and 6,7-dihydoxybergamottin were 16 and 23 ^mol/L in grapefruit juice. The authors concluded that Seville orange juice and grapefruit juice interact with felodipine by a common mechanism (137).

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