Review article. Assessing clinical evidence of drug interactions between citrus juices and cyclosporine

Open access


Background: Previous studies have demonstrated that grapefruit juice increased the bioavailability of cyclosporine; however, the results from the literature are inconsistent. Other citrus fruits such as pomelo or orange juice had variable effects on the bioavailability of cyclosporine.

Objective: To assess the effect of grapefruit juice and other types of citrus juice on oral bioavailability of cyclosporine in humans using meta-analysis.

Methods: We conducted a meta-analysis of placebo-controlled studies evaluating the effects of citrus juices on bioavailability of cyclosporine. The studies were identified in PubMed, Cochrane CENTRAL, CINAHL, ISI Web of Knowledge, Psych Info International, Pharmaceutical Abstract (IPA), and reference lists of relevant papers. The weighted-mean difference (WMD) was calculated for net changes in the area under the curve (AUC) of cyclosporine. All studies conducted as placebo-controlled crossover studies in humans to compare the effect of citrus juices and control (drinking water) on AUC of cyclosporine and/or Cmin,ss were reviewed. All studies included were evaluated and extracted independently, and discrepancies were resolved through discussion.

Results: Eighteen studies were identified. A subgroup analysis suggested that grapefruit juice significantly increased AUC of cyclosporine (WMD = 1762.5 ng⋅h/ml, 95%CI = 1178.9-2346.0 ng⋅h/ml, p < 0.001). While a meta-analysis of all other types of citrus juices (tangerine juice, Seville orange juice, sweet orange juice, and citrus soda) except pomelo juice revealed no effect on the AUC of cyclosporine (WMD = -181.0 ng⋅h/ml, 95%CI = -582.8-220.9 ng⋅h/ml, p > 0.5), a study of pomelo juice indicated a significant increase in the AUC of cyclosporine.

Conclusions: Grapefruit juice intake increases oral bioavailability of cyclosporine in both healthy volunteers and renal transplant patients, whereas all other types of citrus juices may not have an influence on the oral bioavailability of cyclosporine. Current evidence suggests that pomelo juice may be able to increase cyclosporine oral bioavailability.

1. Bowers LD. Therapeutic monitoring for cyclosporine: Difficulties in establishing a therapeutic window. Clin Biochem. 1991; 24:81-7.

2. Armstrong VW, Oellerich M. New developments in the immunosuppressive drug monitoring of cyclosporine, tacrolimus, and azathioprine. Clin Biochem. 2001 34:9-16.

3. Nowack R. Review article: cytochrome P450 enzyme, and transport protein mediated herb-drug interactions in renal transplant patients: grapefruit juice, St John’s Wort - and beyond!. Nephrology (Carlton). 2008;13:337-47.

4. Paine MF, Widmer WW, Pusek SN, Beavers KL, Criss AB, Snyder J, et al. Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine. Am J Clin Nutr. 2008; 87:863-71.

5. Guo L-Q, Fukuda K, Ohta T, Yamazoe Y. Role of Furanocoumarin Derivatives on Grapefruit Juice- Mediated Inhibition of Human CYP3A Activity. Drug Metab Dispos. 2000; 28:766-71.

6. Fukuda K, Ohta T, Yamazoe Y. Grapefruit component interacting with rat and human P450 CYP3A: possible involvement of non-flavonoid components in drug interaction. Biol Pharm Bull. 1997; 20:560-4.

7. Fukuda K, Ohta T, Oshima Y, Ohashi N, Yoshikawa M, Yamazoe Y. Specific CYP3A4 inhibitors in grapefruit juice: furocoumarin dimers as components of drug interaction. Pharmacogenetics. 1997; 7:391-6.

8. He K, Iyer KR, Hayes RN, Sinz MW, Woolf TF, Hollenberg PF. Inactivation of Cytochrome P450 3A4 by Bergamottin, a Component of Grapefruit Juice. Chem Res Toxicol. 1998; 11:252-9.

9. Tassaneeyakul W, Guo L-Q, Fukuda K, Ohta T, Yamazoe Y. Inhibition Selectivity of Grapefruit Juice Components on Human Cytochromes P450. Archives of Biochemistry and Biophysics. 2000; 378:356-63.

10. Edwards DJ, Bernier SM. Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice. Life Sciences. 1996; 59:1025-30.

11. Honda Y, Ushigome F, Koyabu N, Morimoto S, Shoyama Y, Uchiumi T, et al. Effects of grapefruit juice and orange juice components on P-glycoproteinand MRP2-mediated drug efflux. Br J Pharmacol. 2004; 143:856-64.

12. Lim S-L, Lim L-Y. Effects of citrus fruit juices on cytotoxicity and drug transport pathways of Caco-2 cell monolayers. Int J Pharm. 2006; 307:42-50.

13. Romiti N, Tramonti G, Donati A, Chieli E. Effects of grapefruit juice on the multidrug transporter Pglycoprotein in the human proximal tubular cell line HK-2. Life Sciences. 2004; 76:293-302.

14. Ohnishi A, Matsuo H, Yamada S, Takanaga H, Morimoto S, Shoyama Y, et al. Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on the activity of cytochrome P450 3A4. Br J Pharmacol. 2000; 130: 1369-77.

15. Takanaga H, Ohnishi A, Yamada S, Matsuo H, Morimoto S, Shoyama Y, et al. Polymethoxylated Flavones in Orange Juice Are Inhibitors of Pglycoprotein but Not Cytochrome P450 3A4. J Pharmacol Exp Ther. 2000; 293:230-6.

16. Egashira K, Ohtani H, Itoh S, Koyabu N, Tsujimoto M, Murakami H, et al. Inhibitory effects of pomelo on the metabolism of tacrolimus and the activities of CYP3A4 and P-glycoprotein. Drug Metab Dispos. 2004; 32:828-33.

17. Edwards DJ, Fitzsimmons ME, Schuetz EG, Yasuda K, Ducharme MP, Warbasse LH, et al. 6',7'- dihydroxybergamottin in grapefruit juice and seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and p-glycoprotein. Clin Pharmacol Ther. 1999; 65:237-44.

18. Malhotra S, Bailey DG, Paine MF, Watkins PB. Seville orange juice-felodipine interaction: Comparison with dilute grapefruit juice and involvement of furocoumarins[ast]. Clin Pharmacol Ther. 2001; 69: 14-23.

19. Hou Y-C, Hsiu S-L, Tsao C-W, Wang Y-H, Chao P-DL. Acute incation of toxication of cyclosporin caused by coadministration of decoctions of the fruits of Citrus aurantium and the pericarps of Citrus grandis. Planta Med. 2000; 66:653-5.

20. Grenier J, Fradette C, Morelli G, Merritt GJ, Vranderick M, Ducharme MP. Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans. Clin Pharmacol Ther. 2006; 79:255-62.

21. Castillo JREd, Elsener J, Martineau GP. Pharmacokinetic modeling of in-feed tetracyclines in pigs using a meta-analytic compartmental approach. Swine Health Prod. 1998; 6:189-202.

22. Bistrup C, Nielsen FT, Jeppesen UE, Dieperink H. Effect of grapefruit juice on Sandimmun Neoral(R) absorption among stable renal allograft recipients. Nephrol Dial Transplant. 2001; 16:373-7.

23. Herlitz H, Edgar B, Hedner T, Lidman K, Karlberg I. Grapefruit juice: a possible source of variability in blood concentration of cyclosporin A. Nephrol Dial Transplant. 1993; 8:375.

24. Min DI, Ku YM, Perry PJ, Ukah FO, Ashton K, Martin MF, et al. Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients. Transplantation Proceedings. 1996; 62: 123-5.

25. Proppe DG, Hoch OD, McLean AJ, Visser KE. Influence of chronic ingestion of grapefruit juice on steady-state blood concentrations of cyclosporine A in renal transplant patients with stable raft function. Br J Clin Pharmacol. 1995; 39:337-8.

26. Proppe DG, Visser KE, Bartels R, Hoch OD, Meyer H, McLean AJ. Grapefruit juice selectively modifies cyclosporin A metabolite patterns in renal transplant patients. Clinic Pharmacol Ther. 1996; 59:138.

27. Ducharme MP, Provenzano R, Dehoorne-Smith M, Edwards DJ. Trough concentrations of cyclosporine in blood following administration with grapefruit juice. Br J Clin Pharmacol. 1993; 36:457-9.

28. Ducharme MP, Warbasse LH, Edwards DJ. Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clin Pharmacol Ther. 1995; 57:485-91.

29. Ku YM, Min DI, Flanigan M. Effect of grapefruit juice on the pharmacokinetics of microemulsion cyclosporine and its metabolite in healthy volunteers: does the formulation difference matter?. J Clin Pharmacol. 1998; 38:959-65.

30. Lee M, Min DI, Ku YM, Flanigan M. Effect of grapefruit juice on pharmacokinetics of microemulsion cyclosporine in African American subjects compared with Caucasian subjects: does ethnic difference matter? J Clin Pharm. 2001; 41:317-23.

31. Schwarz UI, Johnston PE, Bailey DG, Kim RB, Mayo G, Milstone A. Impact of citrus soft drinks relative to grapefruit juice on ciclosporin disposition. Br J Clin Pharmacol. 2005; 62:485-91.

32. Yee GC, Stanley DL, Pessa LJ, Costa TD, Beltz SE, Ruiz J, et al. Effect of grapefruit juice on blood cyclosporin concentration. Lancet. 1995; 345:955-6.

33. Brunner LJ, Pai KS, Munar MY, Lande MB, Olyaei AJ, Mowry JA. Effect of grapefruit juice on cyclosporin. A pharmacokinetics in pediatric renal transplant patients. Pediatr Transplant. 2000; 4:313-21.

34. Hollander AA, van Rooij J, Lentjes GW, Arbouw F, van Bree JB, Schoemaker RC, et al. The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients. Clin Pharmacol Ther. 1995; 57:318-24.

35. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary?. Controlled Clin Trials. 1996; 17: 1-12.

36. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315:629-34.

37. Begg CB, Mazumdar M. Operating Characteristics of a Rank Correlation Test for Publication Bias. Biometrics. 1994; 50:1088-101.

38. Ameer B, Weintraub RA. Drug interactions with grapefruit juice. Clin Pharmacokinet. 1997; 33:103-21.

39. Bailey DG, Arnold JM, Spence JD. Grapefruit juice and drugs. How significant is the interaction? Clin Pharmacokinet. 1994; 26:91-8.

40. Dahan A, Altman H. Food-drug interaction: grapefruit juice augments drug bioavailability:mechanism, extent and relevance. Eur J Clin Nutr. 2004; 58:1-9.

41. Haddad A, Davis M, Lagman R. The pharmacological importance of cytochrome CYP3A4 in the palliation of symptoms: review and recommendations for avoiding adverse drug interactions. Supportive Care Cancer. 2007; 15:251-7.

42. Hebert MF. Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv Drug Deliv Rev. 1997; 27:201-14.

43. Huang S-M, Hall SD, Watkins P, Love LA, Serabjit- Singh C, Betz JM, et al. Drug Interactions with Herbal Products and Grapefruit Juice: A Conference Report[ast]. Clin Pharmacol Ther. 2004; 75:1-12.

44. Ioannides C. Drug-phytochemical interactions. Inflammopharmacology. 2003; 11:7-42.

45. Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc. 2000; 75:933-42.

46. Lo A, Burckart GJ. P-glycoprotein and drug therapy in organ transplantation. J Clin Pharmacol. 1999; 39: 995-1005.

47. Mertens-Talcott SU, Zadezensky I, De Castro WV, Derendorf H, Butterweck V. Grapefruit-Drug Interactions: Can Interactions With Drugs Be Avoided?. J Clin Pharmacol. 2006; 46:1390-416.

48. Schmidt LE, Dalhoff K. Food-drug interactions. Drugs [Review]. 2002; 62:1481-502.

49. Zhou SF, Lim LY, Chowbay B. Herbal modulation of P-glycoprotein. Drug Metab Rev. 2004; 36:57-104.

50. Saito M, Hirata-Koizumi M, Matsumoto M, Urano T, Hasegawa R. Undesirable effects of citrus juice on the pharmacokinetics of drugs: Focus on recent studies. Drug Safety. 2006; 28:677-94.

51. Bailey DG. Sun drop citrus soda and cyclosporine interaction: comments on causality and recommendations. Transplant Proc. 2005; 79:747.

52. Johnston A, Holt DW. Comment on: Lancet. 1995 Apr 15;345(8955):955-6. Effect of grapefruit juice on blood cyclosporin concentration. Lancet. 1995; 346: 122-3.

53. Paine MF, Oberlies NH. Clinical relevance of the small intestine as an organ of drug elimination: drug-fruit juice interactions. Expert Opin Drug Metab Toxicol. 2007; 3:67-80.

54. Rodriguez-Proteau R, Mata JE, Miranda CL, Fan Y, Brown JJ, Buhler DR. Plant polyphenols and multidrug resistance: effects of dietary flavonoids on drug transporters in Caco-2 and MDCKII-MDR1 cell transport models. Xenobiotica. 2006; 36:41-58.

55. Fang SH, Hou YC, Hsiu SL, Chao PDL. Effects of Citrus grandis peels on cyclosporin concentration and immune responses in mice. J Food Drug Anal. 2006; 14:166-73.

56. Wang M, Hou Y-C, Tsai S, Hsiu S-L, Wen K, Chao P-DL. Effects of coadministrations of unripe fruits and ripe peels of Citrus aurantium on cyclosporine pharmacokinetics in rats. JFDA. 2007; 15:265-70.

57. Hou YC. Effects of citrus herbs on cyclosporin pharmacokinetics in rats and pigs (PDM-P-121). FIP World Congress. 2002; 62:48.

58. Johnston PE, Milstone A. Probable interaction of bergamottin and cyclosporine in a lung transplant recipient. Transplant Proc. 2005; 79:746.

59. Mehrsai AR, Pourmand G, Mansour D, Zand S, Rezaali A. Effect of grapefruit juice on serum concentration of cyclosporine in Iranian renal transplant patients. Transplant Proc. 2003; 35: 2739-41.

60. Sorkhi H, Moghadamnia AA, Oaliaee F, Pouramir M, Firoozjahi AR, Pasha AA, et al. Effect of tangerine juice on cyclosporine levels in renal transplant children. Pediatr Nephrol. 2008; 23:499-501.

61. Sorkhi H, Oliaei F, Moghadamnia AA, Pouramin M, Firoozjahi AR. Effect of Orange and Tangerine Juice on Cyclosporine Levels in Renal Transplant Recipients. Transplant Proc. 2007; 39:1228-30.

62. Brunner LJ, Munar MY, Vallian J, Wolfson M, Stennett DJ, Meyer MM, et al. Interaction between cyclosporine and grapefruit juice requires long-term ingestion in stable renal transplant recipients. Pharmacotherapy. 1998; 18:23-9.

63. Hermann M, Asberg A, Reubsaet JL, Sather S, Berg KJ, Christensen H. Intake of grapefruit juice alters the metabolic pattern of cyclosporin A in renal transplant recipients. Int J Clin Pharmacol Ther. 2002; 40:451-6.

64. Emilia G, Longo G, Bertesi M, Gandini G, Ferrara L, Valenti C. Clinical Interaction Between Grapefruit Juice and Cyclosporine: Is There any Interest for the Hematologists?. Blood. 1998; 91:362-3.

65. Akhlaghi F, Trull AK. Distribution of Cyclosporin in Organ Transplant Recipients. Clin Pharmacokinet. 2002; 41:615-37.

66. Fukuda K, Guo L, Ohashi N, Yoshikawa M, Yamazoe Y. Amounts and variation in grapefruit juice of the main components causing grapefruit-drug interaction. J Chromatogr B Biomed Sci Appl. 2000; 741:195-203.

67. Friman S, Baeckman L. A new microemulsion formulation of cyclosporin: Pharmacokinetic and clinical features. Clin Pharmacokinet. 1996; 30:181-93.

68. Lohitnavy M, Lu Y, Lohitnavy O. A pharmacokinetic model of the gastrointestinal tract consisting of two segments can describe the concentration-time course of itraconazole. Int J Clin Pharmacol Ther. 2006; 44: 394-6.

69. Lohitnavy M, Lu Y, Lohitnavy O, Chubb LS, Hirono S, Yang RSH. A Possible Role of Multidrug Resistance- Associated Protein 2 (Mrp2) in Hepatic Excretion of PCB126, an Environmental Contaminant: PBPK/PD Modeling. Toxicol Sci. 2008; 104:27-39.

Journal Information

IMPACT FACTOR 2017: 0.209
5-year IMPACT FACTOR: 0.243

CiteScore 2017: 0.24

SCImago Journal Rank (SJR) 2017: 0.162
Source Normalized Impact per Paper (SNIP) 2017: 0.173


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 67 67 14
PDF Downloads 28 28 5