Pomegranate Juice for CYP3A4- and CYP2C9-Mediated Drugs Metabolism

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This entry is adapted from the peer-reviewed paper 10.3390/molecules28052117

The Punica granatum L. (pomegranate) fruit juice contains large amounts of polyphenols, mainly tannins such as ellagitannin, punicalagin, and punicalin, and flavonoids such as anthocyanins, flavan-3-ols, and flavonols. These constituents have high antioxidant, anti-inflammatory, anti-diabetic, anti-obesity, and anticancer activities. Because of these activities, many patients may consume pomegranate juice (PJ) with or without their doctor’s knowledge. This may raise any significant medication errors or benefits because of food-drug interactions that modulate the drug’s pharmacokinetics or pharmacodynamics.

cytochrome P450 (CYP450, CYP3A and CYP2C9) pharmacokinetics pharmacodynamics pomegranate juice

1. Introduction

The preclinical studies showing the impact of Punica granatum L. (pomegranate) on the pharmacokinetics of drugs metabolized by CYP3A4 and CYP2C9 are summarized in Table 1.

Table 1. Preclinical studies investigating the effect of oral administration of pomegranate juice on the PK or PK-PD related to CYP3A4 and CYP2C9-mediated drugs.

Pomegranate Dose	Drug	Animal Species	PK/PD Effects	Drug’s Analytical Technique- Biological Sample *	Reference
Pomegranate juice (2 mL) 1 h before the drug	Carbamazepine (50 mg/kg)	Rats	AUC increased, but no effect on the elimination half-life	HPLC-UV Plasma	^[1]
Pomegranate juice (3 mL) administered 1 h before the drug	Tolbutamide (20 mg/kg)	Rats	AUC increased, but no effect on the elimination half-life	HPLC-UV Serum	^[2]
Pomegranate juice (10 mL/kg) for 7 days	Buspirone (10 mg/kg)	Rabbits	AUC, C_max, and elimination half-life increased	HPLC-UV Serum	^[3]
Pomegranate juice, single dose Pomegranate juice, multiple doses for 1 week	Nitrendipine (10 mg/kg)	Rabbits	No PK changes AUC and C_max increased, but no effect on the elimination half-life	HPLC-UV Plasma	^[4]
Pomegranate juice, single dose (3 mL/rat) Pomegranate juice, multiple doses (3 mL/rat/day for 7 days)	Nitrendipine (10 mg/kg)	Rats	AUC and C_max increased, but no effect on the elimination half-life AUC and C_max increased, but no effect on the elimination half-life	HPLC-UV Plasma	^[5]
Pomegranate juice was administered at 5 mL/kg dose 30 min before drug administration or multiple doses twice a day for 2 days	Metronidazole (14 mg/kg)	Rats	No PK changes from a single dose. Multiple doses of Pomegranate increased AUC and C_max	HPLC-MS Serum	^[6]
Pomegranate juice was added to the drinking water 16 h before sildenafil administration, and then each group of rats received 2, 4, 6, and 8 mL of pomegranate juice when sildenafil was administered.	Sildenafil (5 mL/kg)	Rats	AUC increased, and T_max delayed	HPLC-UV Plasma	^[7]
Pomegranate juice One dose (0.5 mL, 1 mL, and 2 mL/200 g) Dose for 15 days (0.5 mL, 1 mL, and 2 mL/200 g/day)	Saquinavir (100 mg/kg) Saquinavir (100 mg/kg) for 15 days	Rats Rats	AUC, C_max, and elimination half-life increased AUC, C_max, and elimination half-life decreased.	HPLC-UV Plasma	^[8]
Pomegranate juice was administered as a single dose of 100 mg/kg for 5 days.	Warfarin (0.5 mg/kg)	Rats	Pomegranate did not change PK, but Prothrombin time and INR increased	HPLC-UV Plasma	^[9]

* HPLC = High Performance Liquid Chromatography; UV = Ultraviolet; MS = Mass Spectroscopy.

2. Pomegranate and Carbamazepine

Carbamazepine is an anticonvulsant medication for treating seizures, nerve pain and bipolar disorders. Carbamazepine metabolism is mediated by CYP3A ^[10]. In rats, a single dose of pomegranate juice (PJ) increased the area under the curve (AUC) and the highest concentration (C_max) of carbamazepine and its metabolite, carbamazepine-10,11-epoxide, compared to water-fed rats ^[1]. The change in PK parameters was similar to grapefruit juice-administered rats ^[1]. In-vitro, increasing doses of PJ inhibited human CYP3A by determining the activity of carbamazepine-10,11-epoxide, and also increasing the preincubation time resulted in inhibiting carbamazepine-10,11-epoxide activity ^[1]. These investigators also observed that the time of CYP3A recovery from a single dose of PJ would be approximately 3 days. These data suggest that a single dose of PJ reduces the intestinal but not hepatic CYP3A metabolism of carbamazepine in rats.

3. Pomegranate and Tolbutamide

Tolbutamide is a sulfonylurea that is used in type-2 diabetes to stimulate insulin secretion. Tolbutamide is a substrate for CYP2C9. In rats, a single dose of PJ increased the tolbutamide AUC 1.2-fold but did not modulate the elimination half-life ^[2]. These data suggest that a single dose of PJ inhibits the intestinal but not the hepatic CYP2C9 metabolism of tolbutamide in rats.

4. Pomegranate and Buspirone

Buspirone is an anxiolytic drug, and it is metabolized by CYP3A. In rabbits following repeated dosing of PJ for 7 days, the buspirone AUC and C_max increased five-fold, and the elimination half-life increased 1.3-fold compared to buspirone alone ^[3]. These data suggest that repeated administration of PJ affects intestinal and liver CYP3A metabolism of buspirone in rats.

5. Pomegranate and Nitrendipine

Nitrendipine is a calcium channel blocker and is used primarily to treat hypertension. The effect of PJ on the PK of nitrendipine was studied in a single-pass intestinal perfusion model and preclinically in rodents. Rabbits pretreated with PJ for 7 days exhibited higher nitrendipine AUC and C_max values but did not show an increased elimination half-life compared to control-treated rabbits ^[4]. However, a single co-administered dose of PJ did not alter the PK parameters of nitrendipine. In rats, PJ administration as a single co-administered dose or 7-day administration increased the AUC and C_max of nitrendipine, but not the elimination half-life, by around two- and five-fold for the AUC and 1.4- and four-fold for the C_max, respectively ^[5]. Since nitrendipine is metabolized in the liver by CYP3A4 ^[11], the above results suggest that PJ reduces intestinal, but not hepatic, metabolism of nitrendipine in rats. Furthermore, using a single-pass intestinal perfusion model, PJ increased permeability, absorption rate constant and nitrendipine absorption. The latter results suggest that PJ enhances the absorption of drugs mediated by P-glycoprotein, such as nitrendipine ^[12].

6. Pomegranate and Metronidazole

Metronidazole is an anti-protozoal and antibiotic drug currently used in intestinal, gynecologic and dental infections and others ^[13]. Multiple dosing, but not a single dose, of PJ, increased C_max and AUC of metronidazole by 1.4 and 2.3 folds, respectively, in rats ^[6]. Metronidazole gets metabolized primarily by CYP2A6, but CYP3A4 plays some role in 2-hydroxymetronidazole formation ^[14]. Thus, it would be expected that a single PJ may have no effect on metronidazole metabolism, but multiple doses might increase the bioavailability of metronidazole.

7. Pomegranate and Sildenafil

Sildenafil is a drug prescribed for the treatment of erectile dysfunction and pulmonary hypertension. In three clinical cases, Senthikumaran et al. (2012) reported that taking PJ with sildenafil prolonged erection episodes beyond orgasm ^[15]. Furthermore, Mallah et al. showed that PJ increased sildenafil bioavailability in rats in a dose-dependent fashion. The area under the curve (AUC) was increased when a higher amount of PJ was given to rats. In addition, T_max was delayed, and the elimination rate of sildenafil was decreased when combined with pomegranate ^[7].

Sildenafil is metabolized mainly by CYP3A4 (79%) and, to a lesser extent, by CYP2C9 (19%) ^[16]. Since pomegranate constituents impair CYP2C9, this may be the main reason for increasing sildenafil bioavailability and therefore prolonging the erection period. In addition, the delay in absorption may be related to pomegranate interaction with CYP3A4.

8. Pomegranate and Saquinavir

Saquinavir is a retroviral protease inhibitor used for human immunodeficiency virus infection treatment. Saquinavir is metabolized by CYP3A4 in the gastrointestinal tract and liver, and also its absorption in the intestinal mucosa is mediated by the efflux transporter P-glycoprotein ^[17]^[18].

In a single-dose treatment of pomegranate and saquinavir, PJ increased saquinavir’s AUC and C_max at the three doses of pomegranate. Also, the elimination half-life was increased. In an ex vivo model, PJ also increased saquinavir transport to the mucosal compartment in a time-dependent manner similar to P-glycoprotein known inhibitors ^[8]. However, following the 15-day administration of saquinavir and PJ, the AUC and C_max parameters were reduced in pomegranate-treated rats in addition to delaying in T_max and reduction in elimination half-life elimination ^[8]. In the latter experimental, however, both pomegranate and saquinavir were administered for 15 days, i.e., two variables were introduced. Therefore, it would be difficult to interpret the PJ effects following prolonged administration since multiple dosing of saquinavir also increased the bioavailability of midazolam, a substrate for CYP3A4 in healthy volunteers ^[19]. In the latter clinical study, 2 weeks of saquinavir increased midazolam’s AUC, C_max, and elimination half-life several-fold and reduced its circulatory metabolite, 1’-hydroxymidazolam ^[19]. The latter study demonstrated that when both CYP3A4-mediated drugs are administered, their bioavailability will be modulated.

9. Pomegranate and Warfarin

Warfarin is widely used as an anticoagulant. As a narrow therapeutic index drug, interactions with juices should be addressed. A case study reported that PJ was the reason for having a stable international normalized ratio (INR) in a patient who took warfarin for several months ^[20]. When the patient stopped taking PJ, her INR became subtherapeutic. In rats, when pomegranate peel extract with 40% ellagic acid was combined with warfarin, INR was increased, but without affecting warfarin pharmacokinetics ^[9]. On the other hand, ellagic acid administration increased the C_max of warfarin ^[9]. In another animal study on PJ interaction with warfarin PK, pomegranate intake increased prothrombin time and INR ^[21]. Warfarin is present in different enantiomers (R and S), and each was found to be metabolized by different sets of enzymes. For instance, R-warfarin is metabolized primarily by CYP1A2, whereas S-warfarin is metabolized primarily by CYP2C9 ^[22]. Since pomegranate was found to inhibit CYP2C9, then it would be expected that pomegranate increases the INR in warfarin-treated patients.

References

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Nagata, M.; Hidaka, M.; Sekiya, H.; Kawano, Y.; Yamasaki, K.; Okumura, M.; Arimori, K. Effects of Pomegranate Juice on Human Cytochrome P450 2C9 and Tolbutamide Pharmacokinetics in Rats. Drug Metab. Dispos. 2006, 35, 302–305.
Kumar, Y.S.; Adukondalu, D.; Latha, A.B.; Vishnu, Y.V.; Ramesh, G.; Kumar, R.S.; Rao, Y.M.; Sarangapani, M. Effect of pomegranate pretreatment on the oral bioavailability of buspirone in male albino rabbits. DARU J. Pharm. Sci. 2011, 19, 266–269.
Voruganti, S.; Rapolu, K.; Tota, S.; Yamsani, S.K.; Yamsani, M.R. Effect of pomegranate juice on the pharmacokinetics of nitrendipine in rabbits. Eur. J. Drug Metab. Pharmacokinet. 2011, 37, 77–81.
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