Journal
XENOBIOTICA
Volume 42, Issue 12, Pages 1163-1169Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/00498254.2012.700428
Keywords
Grapefruit juice; cytochrome P450-3A; furanocoumarin; drug interactions
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Funding
- Ocean Spray Inc.
- Lakeville-Middleboro, MA
- New Varieties Development and Management Corporation (NVDMC) through the Florida Department of Citrus
- Citrus Research and Development Foundation
- National Center for Complementary and Alternative Medicine, National Institutes of Health [F31 AT 006068]
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1. A citrus breeding program aimed at developing low furanocoumarin (FC) grapefruit cultivars provided 40 grapefruit juice (GFJ) samples containing variable concentrations of FC derivatives, established as being mechanism-based (irreversible) inhibitors of human CYP3A isoforms. 2. The principal inhibitory FCs were identified as 6',7'-dihydroxybergamottin, along with a series of dimeric compounds (spiroesters) having high inhibitory potency. 3. A random subset of the GFJ samples (n = 25) were tested as CYP3A inhibitors using an in vitro model based on human liver microsomal metabolism of the index substrate triazolam. The reciprocal values of in vitro 50% inhibitory concentrations (IC50) were highly correlated with concentrations of inhibitory FCs in the GFJ samples (r(2) = 0.96). However the correlations were driven mainly by a few samples having high FC content and high reciprocal IC50 (corresponding to low IC50). Among the rest of the samples, the relationship was less robust. 4. Further study is needed to determine how low the FC content needs to be (or how high the IC50 needs to be) to assure minimal risk of clinical interactions involving GFJ and CYP3A substrate drugs.
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