title: Effect of Low-Furanocoumarin Hybrid Grapefruit Juice Consumption on Midazolam Pharmacokinetics.
abstract: The objectives of this study were to investigate the effect of grapefruit juice low in furanocoumarins on CYP3A activity and to summarize previous findings of enzyme inhibition measured by the metabolism of midazolam after intake of grapefruit juice. Twelve healthy volunteers participated in a prospective, randomized, double-blinded, 3-way crossover clinical study to determine the effect of regular grapefruit juice (RGJ) and a novel, low-furanocoumarin hybrid grapefruit juice (HGJ) on the metabolism of oral midazolam, used as a probe for in vivo CYP3A activity, compared with water as a control. The RGJ was 100% hand-squeezed "Hudson" grapefruit juice, and the HGJ contained low amounts of furanocoumarin constituents. The point estimates (90% confidence intervals) for the RGJ/water midazolam AUC geometric mean ratio was 122% (107-140). The point estimate for the HGJ/water midazolam AUC ratio was within the 80% to 125% bioequivalence range, indicating an absence of interaction. This finding also prompted a systematic review of available evidence on the pharmacokinetic alteration of midazolam by grapefruit juice. Although most studies demonstrated alteration in midazolam pharmacokinetics supporting inhibition of CYP3A activity as a likely mechanism, the cohorts included in these studies and the extent of the pharmacokinetic interaction varied widely. The current study indicated grapefruit juice-drug interaction varies substantially based on patient characteristics and/or grapefruit juice product-related factors, including the amount of furanocoumarin constituents present in the juice.
authors: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA.|School of Pharmacy, Pacific University Oregon, Hillsboro, OR, USA.
authors: Marina
authors: M
authors: Kawaguchi-Suzuki
authors: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA.
authors: Negar
authors: N
authors: Nasiri-Kenari
authors: Department of Health Outcomes and Policy, University of Florida, Gainesville, FL, USA.
authors: Jonathan
authors: J
authors: Shuster
authors: Department of Horticultural Sciences, Citrus Research and Education Center, Lake Alfred, FL, USA.
authors: Fred G
authors: FG
authors: Gmitter
authors: Florida Department of Citrus, Citrus Research and Education Center, Lake Alfred, FL, USA.
authors: Paul
authors: P
authors: Cancalon
authors: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA.
authors: Felipe
authors: F
authors: de Oliveria
authors: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA.
authors: Jennifer
authors: J
authors: Kight
authors: Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA.
authors: Eileen M
authors: EM
authors: Handberg
authors: Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA.
authors: Carl J
authors: CJ
authors: Pepine
authors: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA.
authors: Reginald F
authors: RF
authors: Frye
authors: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA.
authors: Rhonda M
authors: RM
authors: Cooper-DeHoff
mesh_terms: D000328:Adult; D019540:Area Under Curve; D032083:Citrus paradisi; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D018565:Food-Drug Interactions; D000067030:Fruit and Vegetable Juices; D011564:Furocoumarins / Q000008:administration & dosage / Q000494:pharmacology*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D011446:Prospective Studies
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D011564:Furocoumarins; D008874:Midazolam
keywords: CYP3A; drug-food interaction; grapefruit juice; midazolam