Journal article
Assessment of a candidate marker constituent predictive of a dietary substance-drug interaction: case study with grapefruit juice and CYP3A4 drug substrates
The Journal of pharmacology and experimental therapeutics, Vol.351(3), pp.576-584
12/2014
Handle:
https://hdl.handle.net/2376/112700
PMCID: PMC4244582
PMID: 25253884
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.
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- Title
- Assessment of a candidate marker constituent predictive of a dietary substance-drug interaction: case study with grapefruit juice and CYP3A4 drug substrates
- Creators
- Garrett R Ainslie - 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.)Kristina K Wolf - 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.)Yingxin Li - 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.)Elizabeth A Connolly - 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.)Yolanda V Scarlett - 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.)J Heyward Hull - 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 F Paine - 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
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.351(3), pp.576-584
- Academic Unit
- Pharmaceutical Sciences, Department of
- Publisher
- United States
- Grant note
- R01-GM077482 / NIGMS NIH HHS T32 ES007126 / NIEHS NIH HHS T32-ES007126 / NIEHS NIH HHS UL1-R001111 / PHS HHS R01 GM077482 / NIGMS NIH HHS UL1-RR025747 / NCRR NIH HHS UL1 RR025747 / NCRR NIH HHS
- Identifiers
- 99900547331801842
- Language
- English
- Resource Type
- Journal article