title: Effect of blueberry juice on clearance of buspirone and flurbiprofen in human volunteers.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sackler Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Boston, MA 02111, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hanley
authors.forename: Gina
authors.initials: G
authors.lastname: Masse
authors.forename: Jerold S
authors.initials: JS
authors.lastname: Harmatz
authors.forename: Paul F
authors.initials: PF
authors.lastname: Cancalon
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Dolnikowski
authors.forename: Michael H
authors.initials: MH
authors.lastname: Court
authors.forename: David J
authors.initials: DJ
authors.lastname: Greenblatt
mesh_terms: D000328:Adult; D000872:Anthocyanins / Q000032:analysis; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D001628:Beverages / Q000009:adverse effects* / Q000032:analysis; D029798:Blueberry Plants / Q000009:adverse effects* / Q000737:chemistry; D002065:Buspirone / Q000493:pharmacokinetics*; D032083:Citrus paradisi / Q000009:adverse effects / Q000737:chemistry; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000494:pharmacology; D005480:Flurbiprofen / Q000493:pharmacokinetics*; D018565:Food-Drug Interactions; D011564:Furocoumarins / Q000032:analysis; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D010636:Phenols / Q000032:analysis
chemical_list: D000872:Anthocyanins; D065692:Cytochrome P-450 CYP3A Inhibitors; D011564:Furocoumarins; D010636:Phenols; D005480:Flurbiprofen; D015725:Fluconazole; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D002065:Buspirone