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Assessing drug interaction risk of the grapefruit juice component and dietary supplement 6′,7′‐dihydroxybergamottin via physiologically‐based pharmacokinetic modeling and simulation
Author(s) -
Ainslie Garrett Robert,
Gufford Brandon T,
Won Christina S,
Wolf Kristina K,
Paine Mary F
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1103.4
Subject(s) - loperamide , grapefruit juice , chemistry , pharmacokinetics , pharmacology , physiologically based pharmacokinetic modelling , drug interaction , cyp3a , bioavailability , biochemistry , cytochrome p450 , medicine , metabolism , diarrhea
The grapefruit juice (GFJ) component 6′7′‐dihydroxybergamottin (DHB) is an irreversible intestinal CYP3A inhibitor, present in amounts up to 4.7 mg/240 mL GFJ. ‘Pharmacokinetic boosting’ effects of GFJ on drug exposure fueled marketing of DHB as a dietary supplement. DHB product labeling ranges from 50–300 mg, raising concerns for amplified drug interactions. Interaction risk with the CYP3A substrate and μ‐opioid receptor agonist loperamide was assessed via physiologically‐based pharmacokinetic modeling and simulation using Simcyp. Inhibition kinetics of DHB toward loperamide N ‐demethylation were recovered using human intestinal microsomes. Partitioning, binding, and permeability parameters for loperamide and DHB were predicted from physicochemical properties. Results were compared to plasma concentration‐time data from an in‐house clinical GFJ‐loperamide interaction study (3.6 mg DHB/240 mL GFJ; 16 mg loperamide). Effects of higher DHB doses were simulated. Median predicted loperamide AUC (93 nM*h), C max (5.2 nM), and t max (2.6 h) agreed with observed values (101 nM*h, 6.0 nM, and 3.0 h, respectively). Simulations with 50 and 300 mg DHB predicted a 2.2‐and 3.3‐fold median increase in loperamide AUC, respectively. Modeling and simulation informed design of a clinical DHB supplement‐loperamide interaction study and provides a framework for DHB supplement‐drug interaction risk assessment.