Interaction of Citrus Juices with Cyclosporine: Systematic Review and Meta-Analysis.
BACKGROUND
Cyclosporine is an immunosuppressant with narrow therapeutic window, metabolized mainly by cytochrome P450 3A4 (CYP3A4) and minimally by cytochrome P450 3A5 (CYP3A5). Citrus juices such as grapefruit juice (GFJ), orange, lemon, pomelo and lime were known to interact with cyclosporine in several randomized controlled trials. The present review is a systematic compilation and quantitative synthesis on the changes of cyclosporine pharmacokinetics with concomitant citrus juice administration.


METHODS
Electronic databases were searched for randomized controlled trials evaluating the effect of any citrus juice on the pharmacokinetics of cyclosporine comparing with water or placebo in healthy volunteers using appropriate search strategies. Percent mean difference with standard error was used to assess the magnitude of difference in the following outcome measures: area under curve from time of drug administration to 24 h (AUC0-24), area under curve from time of drug administration to infinity (AUC0-∞), maximum concentration (Cmax), time to achieve Cmax(Tmax), elimination half-life (T1/2), clearance (CL), volume of distribution and frequency for adverse drug reactions following administration of cyclosporine. RevMan 5.3 software was used to assess heterogeneity (by I2statistics), use random-effects model and generate pooled results and Forest plot.


RESULTS
A total of 57 studies were obtained with the search strategy, of which seven were found eligible to be included in the present review. The pooled percent mean difference [95 % CI] for GFJ in comparison to controls for AUC0-24, AUC0-∞, Cmaxand Tmaxof cyclosporine was observed to be 53 [43, 64], 53 [45, 62], 24 [12, 36] and 19 [12, 26], respectively. Similarly, pomelo juice was found to significantly increase both AUC0-∞and Cmaxwith the pooled percent mean difference [95 % CI] as 23 [13, 32] and 25 [1, 50], respectively but decrease T1/2{-8 [-15, -1]} of cyclosporine. Orange juice did not alter any of the pharmacokinetic parameter of cyclosporine significantly.


CONCLUSIONS
Citrus juices especially GFJ and pomelo juice were found to significantly increase the plasma exposure of cyclosporine while orange juice did not exhibit any significant interaction with cyclosporine.
Pharmacology, Department of Health Sciences, Fiji National University, Suva, Fiji. skannandr@gmail.com.
Kannan
K
Sridharan
Prosthodontics, Department of Oral Health, Fiji National University, Suva, Fiji.
Gowri
G
Sivaramakrishnan
D001682:Biological Availability; D002957:Citrus / Q000009:adverse effects*; D032083:Citrus paradisi / Q000009:adverse effects; D016572:Cyclosporine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism*; D019317:Evidence-Based Medicine; D000067030:Fruit and Vegetable Juices / Q000009:adverse effects*; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D016032:Randomized Controlled Trials as Topic
D007166:Immunosuppressive Agents; D016572:Cyclosporine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human