title: Assessment of a candidate marker constituent predictive of a dietary substance-drug interaction: case study with grapefruit juice and CYP3A4 drug substrates.
abstract: Dietary substances, including herbal products and citrus juices, can perpetrate interactions with conventional medications. Regulatory guidances for dietary substance-drug interaction assessment are lacking. This deficiency is due in part to challenges unique to dietary substances, a lack of requisite human-derived data, and limited jurisdiction. An in vitro-in vivo extrapolation (IVIVE) approach to help address some of these hurdles was evaluated using the exemplar dietary substance grapefruit juice (GFJ), the candidate marker constituent 6',7'-dihydroxybergamottin (DHB), and the purported victim drug loperamide. First, the GFJ-loperamide interaction was assessed in 16 healthy volunteers. Loperamide (16 mg) was administered with 240 ml of water or GFJ; plasma was collected from 0 to 72 hours. Relative to water, GFJ increased the geometric mean loperamide area under the plasma concentration-time curve (AUC) significantly (1.7-fold). Second, the mechanism-based inhibition kinetics for DHB were recovered using human intestinal microsomes and the index CYP3A4 reaction, loperamide N-desmethylation (KI [concentration needed to achieve one-half kinact], 5.0 ± 0.9 µM; kinact [maximum inactivation rate constant], 0.38 ± 0.02 minute(-1)). These parameters were incorporated into a mechanistic static model, which predicted a 1.6-fold increase in loperamide AUC. Third, the successful IVIVE prompted further application to 15 previously reported GFJ-drug interaction studies selected according to predefined criteria. Twelve of the interactions were predicted to within the 25% predefined criterion. Results suggest that DHB could be used to predict the CYP3A4-mediated effect of GFJ. This time- and cost-effective IVIVE approach could be applied to other dietary substance-drug interactions to help prioritize new and existing drugs for more advanced (dynamic) modeling and simulation and clinical assessment.
authors.affiliation: Curriculum in Toxicology (G.R.A., M.F.P.) and Division of Gastroenterology and Hepatology (Y.V.S.), School of Medicine, and UNC Eshelman School of Pharmacy (K.K.W., Y.L., E.A.C., J.H.H.), The University of North Carolina, Chapel Hill, North Carolina; and Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (G.R.A., M.F.P.).
authors.forename: Garrett R
authors.initials: GR
authors.lastname: Ainslie
authors.affiliation: Curriculum in Toxicology (G.R.A., M.F.P.) and Division of Gastroenterology and Hepatology (Y.V.S.), School of Medicine, and UNC Eshelman School of Pharmacy (K.K.W., Y.L., E.A.C., J.H.H.), The University of North Carolina, Chapel Hill, North Carolina; and Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (G.R.A., M.F.P.).
authors.forename: Kristina K
authors.initials: KK
authors.lastname: Wolf
authors.affiliation: Curriculum in Toxicology (G.R.A., M.F.P.) and Division of Gastroenterology and Hepatology (Y.V.S.), School of Medicine, and UNC Eshelman School of Pharmacy (K.K.W., Y.L., E.A.C., J.H.H.), The University of North Carolina, Chapel Hill, North Carolina; and Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (G.R.A., M.F.P.).
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Curriculum in Toxicology (G.R.A., M.F.P.) and Division of Gastroenterology and Hepatology (Y.V.S.), School of Medicine, and UNC Eshelman School of Pharmacy (K.K.W., Y.L., E.A.C., J.H.H.), The University of North Carolina, Chapel Hill, North Carolina; and Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (G.R.A., M.F.P.).
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Connolly
authors.affiliation: Curriculum in Toxicology (G.R.A., M.F.P.) and Division of Gastroenterology and Hepatology (Y.V.S.), School of Medicine, and UNC Eshelman School of Pharmacy (K.K.W., Y.L., E.A.C., J.H.H.), The University of North Carolina, Chapel Hill, North Carolina; and Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (G.R.A., M.F.P.).
authors.forename: Yolanda V
authors.initials: YV
authors.lastname: Scarlett
authors.affiliation: Curriculum in Toxicology (G.R.A., M.F.P.) and Division of Gastroenterology and Hepatology (Y.V.S.), School of Medicine, and UNC Eshelman School of Pharmacy (K.K.W., Y.L., E.A.C., J.H.H.), The University of North Carolina, Chapel Hill, North Carolina; and Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (G.R.A., M.F.P.).
authors.forename: J Heyward
authors.initials: JH
authors.lastname: Hull
authors.affiliation: Curriculum in Toxicology (G.R.A., M.F.P.) and Division of Gastroenterology and Hepatology (Y.V.S.), School of Medicine, and UNC Eshelman School of Pharmacy (K.K.W., Y.L., E.A.C., J.H.H.), The University of North Carolina, Chapel Hill, North Carolina; and Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (G.R.A., M.F.P.) mary.paine@wsu.edu.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Paine
mesh_terms: D000328:Adult; D001628:Beverages; D015415:Biomarkers / Q000097:blood; D032083:Citrus paradisi; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D018565:Food-Drug Interactions / Q000502:physiology*; D005544:Forecasting; D006801:Humans; D008139:Loperamide / Q000008:administration & dosage / Q000097:blood*; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D011446:Prospective Studies; D013379:Substrate Specificity / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
chemical_list: D015415:Biomarkers; D008139:Loperamide; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human