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 [(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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3-O-Methylglucose / pharmacokinetics
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5-Methoxypsoralen
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Acetates
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Animals
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Caco-2 Cells
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Carbon Radioisotopes
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Cell Line
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Cell Line, Transformed
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Citrus / chemistry*
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Coumarins / chemistry
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Coumarins / pharmacology*
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Cyclosporine / pharmacology
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme Inhibitors*
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Cytochrome P-450 Enzyme System / metabolism
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Dose-Response Relationship, Drug
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Furocoumarins / pharmacology
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Humans
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Hydroxylation / drug effects
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Magnetic Resonance Spectroscopy
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Methoxsalen / analogs & derivatives
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Methoxsalen / pharmacology
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Mixed Function Oxygenases / antagonists & inhibitors*
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Mixed Function Oxygenases / metabolism
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Phenylalanine / pharmacokinetics
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Plant Extracts / chemistry
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Plant Extracts / pharmacology
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Recombinant Proteins / drug effects
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Recombinant Proteins / metabolism
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Testosterone / metabolism
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Tritium
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Vinblastine / pharmacokinetics*
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Acetates
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Carbon Radioisotopes
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Coumarins
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Cytochrome P-450 Enzyme Inhibitors
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Furocoumarins
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Plant Extracts
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Recombinant Proteins
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Tritium
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3-O-Methylglucose
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Testosterone
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Phenylalanine
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5-Methoxypsoralen
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Vinblastine
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ethyl acetate
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Cyclosporine
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Cytochrome P-450 Enzyme System
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Mixed Function Oxygenases
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CYP3A protein, human
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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bergamottin
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bergaptol
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6',7'-dihydroxybergamottin
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Methoxsalen