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

Br J Pharmacol. 2000 Jul;130(6):1369-77. doi: 10.1038/sj.bjp.0703433.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-O-Methylglucose / pharmacokinetics
  • 5-Methoxypsoralen
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Acetates
  • Animals
  • Caco-2 Cells
  • Carbon Radioisotopes
  • Cell Line
  • Cell Line, Transformed
  • Citrus / chemistry*
  • Coumarins / chemistry
  • Coumarins / pharmacology*
  • Cyclosporine / pharmacology
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Dose-Response Relationship, Drug
  • Furocoumarins / pharmacology
  • Humans
  • Hydroxylation / drug effects
  • Magnetic Resonance Spectroscopy
  • Methoxsalen / analogs & derivatives
  • Methoxsalen / pharmacology
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Mixed Function Oxygenases / metabolism
  • Phenylalanine / pharmacokinetics
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology
  • Recombinant Proteins / drug effects
  • Recombinant Proteins / metabolism
  • Testosterone / metabolism
  • Tritium
  • Vinblastine / pharmacokinetics*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Acetates
  • Carbon Radioisotopes
  • Coumarins
  • Cytochrome P-450 Enzyme Inhibitors
  • Furocoumarins
  • Plant Extracts
  • Recombinant Proteins
  • Tritium
  • 3-O-Methylglucose
  • Testosterone
  • Phenylalanine
  • 5-Methoxypsoralen
  • Vinblastine
  • ethyl acetate
  • Cyclosporine
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • bergamottin
  • bergaptol
  • 6',7'-dihydroxybergamottin
  • Methoxsalen