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 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][1]benzopyran-4-yl)-4-hexenyl]oxy]-3,7-dimeth yl- 2-octenyl] oxy]-7H-furo[3,2-g][1]benzopyran-7-one (GF-I-1) and 4-[[6-hydroxy-7-[[4-methyl-I- (1-methylethenyl)-6-(7-oxo-7H-furo[3,2-g][1]benzopyran-4-yl)-4- hexenyl] oxy]-3,7-dimethyl-2-octenyl]oxy]-7H-furo[3,2-g][1]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 6 beta-hydroxylation.
Fukuda
K
K
Division of Drug Metabolism and Molecular Toxicology, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. k-fukuda@tanabe.co.jp
Ohta
T
T
Oshima
Y
Y
Ohashi
N
N
Yoshikawa
M
M
Yamazoe
Y
Y
D001628:Beverages; D002851:Chromatography, High Pressure Liquid; D002957:Citrus / Q000737:chemistry*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D019281:Dimerization; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D011564:Furocoumarins / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D013057:Spectrum Analysis; D013739:Testosterone / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011564:Furocoumarins; D013739:Testosterone; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human