Effect of blueberry juice on clearance of buspirone and flurbiprofen in human volunteers
Article first published online: 15 MAR 2013
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 75, Issue 4, pages 1041–1052, April 2013
How to Cite
Hanley, M. J., Masse, G., Harmatz, J. S., Cancalon, P. F., Dolnikowski, G. G., Court, M. H. and Greenblatt, D. J. (2013), Effect of blueberry juice on clearance of buspirone and flurbiprofen in human volunteers. British Journal of Clinical Pharmacology, 75: 1041–1052. doi: 10.1111/j.1365-2125.2012.04450.x
- Issue published online: 15 MAR 2013
- Article first published online: 15 MAR 2013
- Accepted manuscript online: 3 SEP 2012 06:36AM EST
- Manuscript Accepted: 26 AUG 2012
- Manuscript Received: 1 JUN 2012
- United States Highbush Blueberry Council
- Wild Blueberry Association of North America
- National Institutes of Health. Grant Number: F31 AT 006068
- National Institute of General Medical Sciences, National Institutes of Health. Grant Number: R01 GM 061834
- blueberry juice;
- cytochrome P4502C9;
- cytochrome P4503A;
- grapefruit juice
The present study evaluated the possibility of drug interactions involving blueberry juice (BBJ) and substrate drugs whose clearance is dependent on cytochromes P4503A (CYP3A) and P4502C9 (CYP2C9).
A 50:50 mixture of lowbush and highbush BBJ was evaluated in vitro as an inhibitor of CYP3A activity (hydroxylation of triazolam and dealkylation of buspirone) and of CYP2C9 activity (flurbiprofen hydroxylation) using human liver microsomes. In clinical studies, clearance of oral buspirone and oral flurbiprofen was studied in healthy volunteers with and without co-treatment with BBJ.
BBJ inhibited CYP3A and CYP2C9 activity in vitro, with 50% inhibitory concentrations (IC50) of less than 2%, but without evidence of mechanism-based (irreversible) inhibition. Grapefruit juice (GFJ) also inhibited CYP3A activity, but inhibitory potency was increased by pre-incubation, consistent with mechanism-based inhibition. In clinical studies, GFJ significantly increased area under the plasma concentration−time curve (AUC) for the CYP3A substrate buspirone. The geometric mean ratio (GMR = AUC with GFJ divided by AUC with water) was 2.12. In contrast, the effect of BBJ (GMR = 1.39) was not significant. In the study of flurbiprofen (CYP2C9 substrate), the positive control inhibitor fluconazole significantly increased flurbiprofen AUC (GMR = 1.71), but BBJ had no significant effect (GMR = 1.03).
The increased buspirone AUC associated with BBJ is quantitatively small and could have occurred by chance. BBJ has no effect on flurbiprofen AUC. The studies provide no evidence for concern about clinically important pharmacokinetic drug interactions of BBJ with substrate drugs metabolized by CYP3A or CYP2C9.