Abstract
Purpose
The main purpose of this work was to investigate the effect of pummelo juice on the pharmacokinetics of sildenafil after oral administration.
Methods
This was a comparative, randomized, two-period, two-treatment, two-sequence, single dose, crossover study investigating the effect of pummelo juice on the pharmacokinetics of sildenafil citrate tablets (equivalent to 50 mg sildenafil) in healthy male participants under fasting conditions compared with water as a control. Six healthy normal adult males were administered 50 mg sildenafil with pummelo juice or water at two different periods in a crossover study.
Results
Study results showed that pummelo juice reduced the rate and extent of sildenafil bioavailability to around 60% [maximum plasma concentration (Cmax); from 212.44 ng/ml to 134.07 ng/ml, 90% confidence interval (90% CI) 44.70–89.11, and area under the plasma concentration time curve from zero to infinity (AUC∞); from 564.51 ng.hr/ml to 336.87 ng.hr/ml, 90% CI 39.17–90.92]. This interaction was opposite to that expected and is speculated to be due to either an effect on transporters or a physicochemical interaction between sildenafil and some components of the juice.
Conclusion
Patients should be advised not to drink pummelo juice before or immediately after taking sildenafil.
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References
Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C (1996) Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 8(2):47–52
Nichols DJ, Muirhead GJ, Harness JA (2002) Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol 53(Suppl 1):5S–12S
Walker DK, Ackland MJ, James GC, Muirhead GJ, Rance DJ, Wastall P, Wright PA (1999) Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica 29(3):297–310
Muirhead GJ, Rance DJ, Walker DK, Wastall P (2002) Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil. Br J Clin Pharmacol 53(Suppl 1):13S–20S
Muirhead GJ, Wilner K, Colburn W, Haug-Pihale G, Rouviex B (2002) The effects of age and renal and hepatic impairment on the pharmacokinetics of sildenafil. Br J Clin Pharmacol 53(Suppl 1):21S–30S
Bailey DG, Arnold JM, Munoz C, Spence JD (1993) Grapefruit juice-felodipine interaction: mechanism, predictability, and effect of naringin. Clin Pharmacol Ther 53(6):637–642
Ducharme MP, Warbasse LH, Edwards DJ (1995) Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clin Pharmacol Ther 57(5):485–491
Ku YM, Min DI, Flanigan M (1998) Effect of grapefruit juice on the pharmacokinetics of microemulsion cyclosporine and its metabolite in healthy volunteers: does the formulation difference matter? J Clin Pharmacol 38(10):959–965
Schmiedlin-Ren P, Edwards DJ, Fitzsimmons ME, He K, Lown KS, Woster PM, Rahman A, Thummel KE, Fisher JM, Hollenberg PF, Watkins PB (1997) Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Drug Metab Dispos 25(11):1228–1233
Lee M, Min DI (2001) Determination of sildenafil citrate in plasma by high-performance liquid chromatography and a case for the potential interaction of grapefruit juice with sildenafil citrate. Ther Drug Monit 23(1):21–26
Jetter A, Kinzig-Schippers M, Walchner-Bonjean M, Hering U, Bulitta J, Schreiner P, Sorgel F, Fuhr U (2002) Effects of grapefruit juice on the pharmacokinetics of sildenafil. Clin Pharmacol Ther 71(1):21–29
Egashira K, Ohtani H, Itoh S, Koyabu N, Tsujimoto M, Murakami H, Sawada Y (2004) Inhibitory effects of pomelo on the metabolism of tacrolimus and the activities of CYP3A4 and P-glycoprotein. Drug Metab Dispos 32(8):828–833
Grenier J, Fradette C, Morelli G, Merritt GJ, Vranderick M, Ducharme MP (2006) Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans. Clin Pharmacol Ther 79(3):255–262
Guo LQ, Chen QY, Wang X, Liu YX, Chu XM, Cao XM, Li JH, Yamazoe Y (2007) Different roles of pummelo furanocoumarin and cytochrome P450 3A5*3 polymorphism in the fate and action of felodipine. Curr Drug Metab 8(6):623–630
World Medical Association. Declaration of Helsinki. Ethical principles for medical research involving human subjects. Last amended by the Forty-eighth WMA General Assembly, Somerset West, Republic of South Africa, October 1996. Published online: http://www.wma.net/e/policy/17-c_e.html
Al-Ghazawi M, Tutunji M, Aburuz S (2007) Simultaneous determination of sildenafil and N-desmethyl sildenafil in human plasma by high-performance liquid chromatography method using electrochemical detection with application to a pharmacokinetic study. J Pharm Biomed Anal 43(2):613–618
Sheu MT, Wu AB, Yeh GC, Hsia A, Ho HO (2003) Development of a liquid chromatographic method for bioanalytical applications with sildenafil. J Chromatogr B Anal Technol Biomed Life Sci 791(1–2):255–262
Bailey DG, Dresser GK, Leake BF, Kim RB (2007) Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. Clin Pharmacol Ther 81:495–502
Lee W et al (2005) Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry. J Biol Chem 280:9610–9617
Dresser GK et al (2002) Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther 71:11–20
Soldner A, Christians U, Susanto M, Wacher VJ, Silverman JA, Benet LZ (1999) Grapefruit juice activates P-glycoprotein-mediated drug transport. Pharm Res 16(4):478–485
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The corresponding author thanks Pharsight Corporation for providing the University of Jordan with WinNonlin 5.2 as a PAL user.
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Al-Ghazawi, M.A., Tutunji, M.S. & AbuRuz, S.M. The effects of pummelo juice on pharmacokinetics of sildenafil in healthy adult male Jordanian volunteers. Eur J Clin Pharmacol 66, 159–163 (2010). https://doi.org/10.1007/s00228-009-0738-0
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DOI: https://doi.org/10.1007/s00228-009-0738-0