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

John A. Manthey, Kyung Myung, Susanne Mertens-Talcott, Hartmut Derendorf, Veronika Butterweck, Wilbur W. Widmer


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 Pglycoprotein 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.


coumarins; grapefruit/drug interaction; enzyme inhibition; drug metabolism; drug transport

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Proc. Fla. State Hort. Soc.     ISSN 0886-7283

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