Pomegranate Juice does not Affect the Bioavailability of Cyclosporine in Healthy Thai Volunteers

Abstract

Background: It is still controversial whether pomegranate causes drug interactions. Pomegranate juice has been shown to inhibit CYP3A in-vitro and animal studies. The co-administration pomegranate juice with cyclosporine, a narrow therapeutic drug that is the substrate of CYP3A, which might lead to drug toxicity. The objective of this study is to investigate the effect of pomegranate juice on the pharmacokinetics of cyclosporine in healthy Thai volunteers. Methods: The study design was an open-label, randomized, single dose, crossover study with a 2-week washout period. Each fasting subject received 2 microemulsion tablets of 100 mg of cyclosporine with 500 ml of pomegranate juice (test) or 500 ml of water (control). Serial blood samples were collected up to 24 h after dosing, and blood samples were analyzed for cyclosporine concentrations by using chemiluminescent microparticle immunoassay. Fourteen healthy volunteers completed the study. Results: The 90% confidence intervals for the test/control ratio using logarithmically transformed data of area under the concentration-time curve (AUC) from time zero until the last measured concentration (AUC0-t), AUC from time zero to infinity (AUC0-∞), and maximum concentration (Cmax) were 91.6-105.6, 92.0-105.2 and 82.3-102.5, respectively. The results were within the accepted bioequivalence range for narrow therapeutic index drugs (90-111% for AUC and 80-125% for Cmax). There were no differences in adverse event between groups. Conclusion: Single dose administration of pomegranate juice with cyclosporine did not significantly affect the oral bioavailability of cyclosporine. However, further work is needed to thoroughly evaluate the effect of pomegranate on narrow therapeutic drugs.

Potential profound fluctuation in tacrolimus concentration on consumption of pomegranate rind extract: A Pharmacokinetic Experiment

“…A total of 300 μl of methanol/acetonitrile (50:50, v/v) and 50 μl of ZnSO4 solution were added, and the solution was vortexed for 30 s and centrifuged at 14,000 g (2000 rpm) for 10 min ( Figure 2 ). All the samples were stored at −20°C until further analysis ( Anlamlert and Sermsappasuk, 2020 ).…”

“…Many scientific reports have stated that pomegranate possesses antioxidant, anti-inflammatory ( Karwasra et al, 2019 ), anticancer, antidiabetic, antihypertensive, antifungal, nephroprotective ( Karwasra et al, 2016 ), antimalarial, and antiulcer properties ( Sreekumar et al, 2014 ). Several scientific publications also show that pomegranate juice and peel extracts showed interactions with diverse medications and could markedly increase/decrease the blood concentration of numerous drugs (theophylline, cyclosporine A, warfarin, carbamazepine, and TAC) in patients and rats ( Hidaka et al, 2005 ; Khuu et al, 2013 ; Alanbaki et al, 2019 ; Alnaqeeb et al, 2019 ; Anlamlert and Sermsappasuk, 2020 ). Despite numerous potential pharmacokinetic studies, none of the studies reported on the consumption of pomegranate rind extract (PRE) with TAC altering its pharmacokinetics and the impact of long-term consumption of PRE on TAC.…”

Phytochemistry, Pharmacological Activities, and Drug Interactions of Pomegranate, Punica granatum L. (Punicaceae)

“…The effect from the GFJ was more pronounced (approximately twofold) than from the PJ. The review [12] further showed that most clinical studies that were done later showed no effect of PJ on flurbiprofen (an anti-inflammatory) [74], simvastatin [75], dapoxetine [76], midazolam [77], cyclosporine [78], and artemether [23].…”

“…This shows that the observed preclinical inhibition of CYP3A4 and CYP2C9 by PJ does not necessarily relate to clinical drug interactions in humans [77]. This could be because most of the clinical studies were done using a single dose of PJ [12] and therefore, further clinical studies with prolonged PJ administration of the co-administered drugs are recommended.…”