SPECIFIC CYP3A4 INHIBITORS IN GRAPEFRUIT JUICE - FUROCOUMARIN DIMERS AS COMPONENTS OF DRUG-INTERACTION

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