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

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.