Four components were isolated from grapefruit juice that: inhibit human CYP3A-mediated drug oxidation. The structures of these compounds were identified as furocoumarin derivatives by absorption spectra, APCI-liquid chromatography/tandem mass spectrometry and nuclear magnetic resonance after their purification by reversed-phase high performance liquid chromatography. They include two new furocoumarins, 4-[[6-hydroxy-7-[[1-[(1-hydroxy-1-methyl) ethyl]-4-methyl-6-(7-oxo-7H-furo[3,2-g]benzopyran-4-yl)-4-hexenyl]oxy]-3,7 -dimethyl-2-octenyl] oxy]-7H-furo[3,2-g]benzopyran-7-one (GF-I-1) and 4-[[6-hydroxy-7-[[4-methyl-1-(1-methylethenyl)-6-(7-oxo-7H-furo[3,2 -g]benzopyran-4-yl)-4-hexenyl]oxy]-3,7-dimethyl-2-octenyl]oxy]-7H-furo[3,2 -g]benzopyran-7-one (GF-I-4). These furocoumarins are strong candidates for causative agents of grapefruit juice-mediated drug interaction, because of an inhibition potential that is equal to or stronger than the prototypical CYP3A4 inhibitor, ketoconazole, on liver microsomal testosterone 6β-hydroxylation.
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