Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on the activity of cytochrome P450 3A4.
1. The presence of inhibitors of drug efflux transporters, such as P-glycoprotein (P-gp), in grapefruit juice (GFJ) was confirmed based on the uptake of [(3)H]-vinblastine (VBL) by Caco-2 cells. 2. The uptake of [(3)H]-VBL by Caco-2 cells was significantly increased by the ethyl acetate extract of GFJ as well as by cyclosporin A. The extract was separated on a Cosmosil column and the eluate with 60% methanol increased [(3)H]-VBL uptake, while the activity to inhibit CYP3A4 was greatest in the 70 and 80% eluates. 3. These results show that the major inhibitor of efflux transport of VBL is different from that of CYP3A4. 4. Further separation of the 60% methanol eluate afforded dihydroxybergamottin (DHBG). Both ethyl acetate extract of GFJ and DHBG increased steady-state [(3)H]-VBL uptake by LLC-GA5-COL300 cells. Besides DHBG, other furanocoumarins contained in GFJ, such as bergamottin, FC726, bergaptol and bergapten, increased the steady-state uptake of [(3)H]-VBL by Caco-2 cells. 5. The order of inhibitory potency of these compounds was FC726>DHBG>bergamottin>bergapten>bergaptol . While, the IC(50) values for inhibition of CYP3A4 were 0.075, 0.45, 1.0, 1.0 and >20 microM, respectively. Bergaptol specifically inhibited VBL efflux. 6. DHBG was thus identified as a candidate for inhibitors of VBL transport, together with other furanocoumarins. Moreover, partly involvement of the P-gp inhibition was suggested. 7. Therefore, the inhibition of efflux transport of drugs as well as of drug metabolism by CYP3A4 could be an important cause of drug-GFJ interaction.
Ohnishi
A
A
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Matsuo
H
H
Yamada
S
S
Takanaga
H
H
Morimoto
S
S
Shoyama
Y
Y
Ohtani
H
H
Sawada
Y
Y
D019325:3-O-Methylglucose / Q000493:pharmacokinetics; D000078223:5-Methoxypsoralen; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D000085:Acetates; D000818:Animals; D018938:Caco-2 Cells; D002250:Carbon Radioisotopes; D002460:Cell Line; D002461:Cell Line, Transformed; D002957:Citrus / Q000737:chemistry*; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D011564:Furocoumarins / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008730:Methoxsalen / Q000031:analogs & derivatives / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010649:Phenylalanine / Q000493:pharmacokinetics; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D014316:Tritium; D014747:Vinblastine / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000085:Acetates; D002250:Carbon Radioisotopes; D003374:Coumarins; D065607:Cytochrome P-450 Enzyme Inhibitors; D011564:Furocoumarins; D010936:Plant Extracts; D011994:Recombinant Proteins; D014316:Tritium; D019325:3-O-Methylglucose; D013739:Testosterone; D010649:Phenylalanine; D000078223:5-Methoxypsoralen; D014747:Vinblastine; C007650:ethyl acetate; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C068337:bergamottin; C080771:bergaptol; C104774:6',7'-dihydroxybergamottin; D008730:Methoxsalen