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Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans.
Clin Pharmacol Ther. 2006 Mar; 79(3):255-62.CP

Abstract

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 (AUCt), area under the curve from time 0 to infinity (AUCinf), and maximum blood concentration (Cmax) 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 AUCt and AUCinf and P = .0167 for Cmax; however, only the increase in AUCt 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 AUCt, AUCinf, and Cmax 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.

Authors+Show Affiliations

MDS Pharma Services and Faculté de Pharmacie, Université de Montréal, Montreal, Quebec, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16513449

Citation

Grenier, Julie, et al. "Pomelo Juice, but Not Cranberry Juice, Affects the Pharmacokinetics of Cyclosporine in Humans." Clinical Pharmacology and Therapeutics, vol. 79, no. 3, 2006, pp. 255-62.
Grenier J, Fradette C, Morelli G, et al. Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans. Clin Pharmacol Ther. 2006;79(3):255-62.
Grenier, J., Fradette, C., Morelli, G., Merritt, G. J., Vranderick, M., & Ducharme, M. P. (2006). Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans. Clinical Pharmacology and Therapeutics, 79(3), 255-62.
Grenier J, et al. Pomelo Juice, but Not Cranberry Juice, Affects the Pharmacokinetics of Cyclosporine in Humans. Clin Pharmacol Ther. 2006;79(3):255-62. PubMed PMID: 16513449.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans. AU - Grenier,Julie, AU - Fradette,Caroline, AU - Morelli,Gaetano, AU - Merritt,Gerald J, AU - Vranderick,Manon, AU - Ducharme,Murray P, Y1 - 2006/02/07/ PY - 2005/07/14/received PY - 2005/11/14/accepted PY - 2006/3/4/pubmed PY - 2006/4/6/medline PY - 2006/3/4/entrez SP - 255 EP - 62 JF - Clinical pharmacology and therapeutics JO - Clin Pharmacol Ther VL - 79 IS - 3 N2 - 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 (AUCt), area under the curve from time 0 to infinity (AUCinf), and maximum blood concentration (Cmax) 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 AUCt and AUCinf and P = .0167 for Cmax; however, only the increase in AUCt 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 AUCt, AUCinf, and Cmax 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. SN - 0009-9236 UR - https://www.unboundmedicine.com/medline/citation/16513449/Pomelo_juice_but_not_cranberry_juice_affects_the_pharmacokinetics_of_cyclosporine_in_humans_ L2 - https://doi.org/10.1016/j.clpt.2005.11.010 DB - PRIME DP - Unbound Medicine ER -