Specific CYP3 A4 inhibitors in grapefruit juice: furocoumarin dimers as components of drug interaction

Abstract

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-[[l-[(l-hydroxy-lmethyI) ethyl]-4-methyl-6-(7-oxo-7H-furo[3,2-g][l]benzopyran-4-yl)-4-hexenyl]oxy]-3,7-dimethyl- 2-octenyl] oxy]-7H-furo[3,2-g][l]benzopyran-7-one (GF-I-1) and 4-[[6-hydroxy-7-[[4-methyI-l- (1-methylethenyl)-6-(7-oxo-7H-furo[3,2-g][ 1]benzopyran-4-yI)-4-hexenyl]oxy]-3,7-dimethyl-2-octenyl]oxy]-7H-furo[3,2-g][l]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.