Submitted to: Proceedings of Florida State Horticultural Society
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/6/2006
Publication Date: 4/11/2007
Citation: Manthey, J.A., Myung, K., Mertens-Talcott, S., Derendorf, H., Butterweck, V., Widmer, W. 2006. The isolation of minor-occurring furanocoumarins in grapefruit and analysis of their inhibition of CYP 3A4 and p-glycoprotein transport of talinolol from caco-2 cells. Proceedings of Florida State Horticultural Society. 119:361-366. Interpretive Summary: There are compounds in grapefruit juice that cause the grapefruit/drug interactions in humans. These compounds are called furanocoumarins. The major-occurring furanocoumarins have been isolated, but there are many other minor compounds that have not been isolated and identified. This study includes the isolation and partial characterization of 11 new compounds. A number of these compounds were also shown to be inhibitors of enzymes involved in the grapefruit/drug interactions, and so these compounds contribute to the overall interaction produced in humans. This work is important in understanding the scope of potential chemical structures involved in these important food/drug interactions.
Technical Abstract: The effects of grapefruit juice on the disposition of certain prescription drugs in humans have been mainly attributed to the inhibition of intestinal cytochrome P450 3A4 (CYP 3A4) by linear furanocoumarins. A number of the main furanocoumarins in grapefruit juice have been identified and analyzed for their inhibition of CYP 3A4; yet many of the minor constituents in grapefruit juice remain uncharacterized. In this paper the isolation of eleven of these minor-occurring furanocoumarins is reported, and their diverse chemical structures are analyzed by UV and mass spectroscopy (MS). Most of these compounds are derivatives of bergamottin. These compounds were further tested for their inhibition of P-glycoprotein inhibition of talinolol transport out of Caco-2 cells, and for their in vitro inhibition of CYP 3A4. Inhibition of the P-glycoprotein transport occurred with four of eight compounds tested, with 2 compounds exhibiting significant inhibition of the P-glycoprotein transport at 1 ppm. Many of these compounds were also potent inhibitors of CYP 3A4 compared to the known compounds, bergamottin, 6', 7'-dihydroxybergamottin, and 6', 7'-epoxybergamottin.