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Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans
Author(s) -
Grenier Julie,
Fradette Caroline,
Morelli Gaetano,
Merritt Gerald J.,
Vranderick Ma,
Ducharme Murray P.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.11.010
Subject(s) - cranberry juice , grapefruit juice , bioavailability , pharmacokinetics , crossover study , cmax , pharmacology , chemistry , oral administration , cyp3a4 , ciclosporin , medicine , food science , placebo , cytochrome p450 , chemotherapy , biochemistry , metabolism , alternative medicine , urinary system , pathology
Background Cyclosporine (INN, ciclosporin) is a cytochrome P450 (CYP) 3A and P‐glycoprotein (P‐gp) substrate whose bioavailability increases when administered with grapefruit juice. It is unknown whether pomelo, a closely related citrus fruit, interacts with cyclosporine in humans. In addition, a case study reports that cranberry juice interacts with warfarin, a drug with a narrow therapeutic range. Cranberries have a high content of flavonoids, compounds with various metabolic effects, including interaction with P‐gp in vitro. Although the effect of flavonoids is less evident in vivo, cranberry juice has become a very popular beverage, and it was deemed important to investigate whether it has an effect on the disposition of cyclosporine, another drug with a narrow therapeutic range. Methods In an open‐label, randomized, 3‐way crossover study with a 14‐day washout period between each dose, 12 healthy male volunteers received single oral 200‐mg doses of cyclosporine according to the following regimens: 200 mg cyclosporine administered with 240 mL of pomelo juice, cranberry juice, or water under fasting conditions. Multiple whole blood samples were collected up to 36 hours after each dose. Concentrations were determined via a liquid chromatography–tandem mass spectrometry method. Results Administration of pomelo juice with cyclosporine increased the area under the curve from time 0 to the last measurable concentration (AUC t ), area under the curve from time 0 to infinity (AUC inf ), and maximum blood concentration (C max ) of cyclosporine with ratios of least squares means of 119.4% (95% confidence interval [CI], 113.4%‐125.8%), 118.9% (95% CI, 113.8%‐124.3%), and 112.1% (95% CI, 102.3%‐122.8%), respectively. All 3 variables exhibited statistically significant increases (with Bonferroni adjustment), with P = .0001 for AUC t and AUC inf and P = .0167 for C max ; however, only the increase in AUC t was judged to be clinically significant with a 95% CI outside the 80% to 125% boundaries. Cranberry juice had no clinically significant effect on the overall disposition of cyclosporine. After administration of cyclosporine with cranberry juice, the ratios of least squares means for AUC t , AUC inf , and C max for cyclosporine were 95.0% (95% CI, 90.3%‐100.1%), 93.4% (95% CI, 89.2%‐97.8%), and 95.2% (95% CI, 86.9%‐104.2%), respectively. Conclusion These results suggest that pomelo juice increases the bioavailability of cyclosporine, possibly by inhibiting CYP3A or P‐gp activity (or both) in the gut wall. However, drinking a glass of cranberry juice does not appear to significantly influence the disposition of cyclosporine. Clinical Pharmacology & Therapeutics (2006) 79 , 255–262; doi: 10.1016/j.clpt.2005.11.010