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 [H-3]-vinblastine (VBL) by Caco-2 cells. 2 The uptake of [H-3]-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 [H-3]-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 [H-3]-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 [H-3]-VBL by Caco-2 cells. 5 The order of inhibitory potency of these compounds was FC726 > DHBG > bergamottin > bergapten> bergaptol. While, the IC50 values for inhibition of CYP3A4 were 0.075, 0.45, 1.0, 1.0 and >20 mu M, 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.