title: Effect of 2 weeks' consumption of pomegranate juice on the pharmacokinetics of a single dose of midazolam: an open-label, randomized, single-center, 2-period crossover study in healthy Japanese volunteers.
abstract: BACKGROUND
  It has been reported that pomegranate juice significantly increased the AUC of orally administered carbamazepine in rats, which suggests that pomegranate may inhibit the cytochrome P450 3A (CYP3A)-mediated carbamazepine metabolism.
  
  
  OBJECTIVE
  The aim of the present study was to clarify the effect of repeated consumption of pomegranate juice on CYP3A activity by assessing the pharmacokinetics of midazolam, a typical CYP3A probe drug, and its metabolites in healthy volunteers.
  
  
  METHODS
  An open-label, randomized, single-center, 2-period crossover study was conducted on healthy Japanese volunteers. Each subject received 200 mL of pomegranate juice twice daily for 2 weeks. On day 14, they were administered 15 μg/kg midazolam orally with either pomegranate juice or water. Plasma concentrations and urinary excretions of midazolam, 1'-hydroxymidazolam, and 4-hydroxymidazolam were determined up to 24 hours using LC/MS/MS and analyzed by a noncompartmental method.
  
  
  RESULTS
  Sixteen subjects (11 men and 5 women) were enrolled and completed the study. The mean (SD) age was 24.1 (4.8) years (range 22-40), mean body weight was 62.9 (8.8) kg (range 45.6-79.9). Differences in the mean AUC(0-∞) were 12.7 (4.4) and 14.2 (6.6) ng/mL/h in pomegranate juice and control groups, respectively (geometric mean ratio: 1.02 [95% CI, 0.95-1.09]; P = 0.40). Differences in C(max) for midazolam did not reach the level of statistical significance (5.1 [1.7] vs 5.0 [2.0] ng/mL, geometric mean ratio: 0.95 [95% CI, 0.79-1.11]; P = 0.68). Excretions of 1'-hydroxymidazolam (P = 0.34) and 4-hydroxymidazolam (P = 0.32) were not significantly altered by ingestion of pomegranate juice.
  
  
  CONCLUSIONS
  In this small Japanese adult volunteer population receiving single subtherapeutic doses of midazolam, 2 weeks' consumption of pomegranate juice did not significantly alter the pharmacokinetic profile of midazolam compared with that of the control. Protocol identifier: UMIN000004459.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Shingen
authors.initials: S
authors.lastname: Misaka
authors.forename: Reiko
authors.initials: R
authors.lastname: Nakamura
authors.forename: Shinya
authors.initials: S
authors.lastname: Uchida
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Norio
authors.initials: N
authors.lastname: Takahashi
authors.forename: Naoki
authors.initials: N
authors.lastname: Inui
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kosuge
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001628:Beverages; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D007564:Japan; D029561:Lythraceae / Q000737:chemistry*; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam