Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on the activity of cytochrome P450 3A4

Ayako Ohnishi, Hirotami Matsuo, Shiho Yamada, Hitomi Takanaga, Satoshi Morimoto, Yukihiro Shoyama, Hisakazu Ohtani, Yasufumi Sawada

Research output: Contribution to journalArticle

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Abstract

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 [3H]-vinblastine (VBL) by Caco-2 cells. 2. The uptake of [3H]-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 [3H]-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 [3H]-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 [3H]-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 μM, 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.

Original languageEnglish
Pages (from-to)1369-1377
Number of pages9
JournalBritish Journal of Pharmacology
Volume130
Issue number6
DOIs
Publication statusPublished - Jan 1 2000

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Citrus paradisi
Cytochrome P-450 CYP3A
Caco-2 Cells
Vinblastine
P-Glycoprotein
Pharmaceutical Preparations
Methanol
Furocoumarins
Cyclosporine
Inhibitory Concentration 50

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on the activity of cytochrome P450 3A4. / Ohnishi, Ayako; Matsuo, Hirotami; Yamada, Shiho; Takanaga, Hitomi; Morimoto, Satoshi; Shoyama, Yukihiro; Ohtani, Hisakazu; Sawada, Yasufumi.

In: British Journal of Pharmacology, Vol. 130, No. 6, 01.01.2000, p. 1369-1377.

Research output: Contribution to journalArticle

Ohnishi, Ayako ; Matsuo, Hirotami ; Yamada, Shiho ; Takanaga, Hitomi ; Morimoto, Satoshi ; Shoyama, Yukihiro ; Ohtani, Hisakazu ; Sawada, Yasufumi. / Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on the activity of cytochrome P450 3A4. In: British Journal of Pharmacology. 2000 ; Vol. 130, No. 6. pp. 1369-1377.
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abstract = "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 [3H]-vinblastine (VBL) by Caco-2 cells. 2. The uptake of [3H]-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 [3H]-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 [3H]-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 [3H]-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 μM, 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.",
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T1 - Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on the activity of cytochrome P450 3A4

AU - Ohnishi, Ayako

AU - Matsuo, Hirotami

AU - Yamada, Shiho

AU - Takanaga, Hitomi

AU - Morimoto, Satoshi

AU - Shoyama, Yukihiro

AU - Ohtani, Hisakazu

AU - Sawada, Yasufumi

PY - 2000/1/1

Y1 - 2000/1/1

N2 - 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 [3H]-vinblastine (VBL) by Caco-2 cells. 2. The uptake of [3H]-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 [3H]-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 [3H]-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 [3H]-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 μM, 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.

AB - 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 [3H]-vinblastine (VBL) by Caco-2 cells. 2. The uptake of [3H]-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 [3H]-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 [3H]-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 [3H]-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 μM, 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.

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