Grapefruit juice activates P-glycoprotein-mediated drug transport.
OBJECTIVE
Grapefruit juice (GJ) is known to increase the oral bioavailability of many CYP3A-substrates by inhibiting intestinal phase-I metabolism. However, the magnitude of AUC increase is often insignificant and highly variable. Since we earlier suggested that CYP3A and P-glycoprotein (P-gp) form a concerted barrier to drug absorption, we investigated the role of P-gp in GJ-drug interactions.


METHODS
The transcellular bidirectional flux of drugs that are (i) CYP3A-and/or P-gp substrates (Vinblastine, Cyclosporine, Digoxin, Fexofenadine, Losartan) or that are (ii) primary CYP3A-substrates (Felodipine, Nifedipine) was evaluated across MDCK-MDR1 cell monolayers with or without GJ, verifying monolayer integrity at all times.


RESULTS
While both apical-to-basal (A-B) and basal-to-apical (B-A) fluxes of all CYP3A/P-gp substrates tested were increased in the presence of GJ, the resulting net efflux (B-A/A-B) was in all cases significantly greater with GJ than control (Vin, 28.0 vs. 5.1; CsA, 9.9 vs. 2.8; Dig, 22. 9 vs. 14.7, Fex, 22.3 vs. 11.1, Los, 39.6 vs. 26). In contrast, no such GJ flux effect was observed with Fel and Nif, substrates of CYP3A only (2 vs. 1.7 and 1.2 vs. 1.3).


CONCLUSIONS
GJ significantly activates P-gp-mediated efflux of drugs that are substrates of P-gp, potentially partially counteracting the CYP3A-inhibitory effects of GJ.
Soldner
A
A
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco 94143-0446, USA.
Christians
U
U
Susanto
M
M
Wacher
V J
VJ
Silverman
J A
JA
Benet
L Z
LZ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases; D001628:Beverages; D001682:Biological Availability; D001693:Biological Transport, Active; D018938:Caco-2 Cells / Q000378:metabolism; D002478:Cells, Cultured; D002957:Citrus; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004234:Diuretics, Osmotic / Q000493:pharmacokinetics; D004285:Dogs; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008353:Mannitol / Q000493:pharmacokinetics; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism; D010599:Pharmacokinetics; D014747:Vinblastine / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D065607:Cytochrome P-450 Enzyme Inhibitors; D004234:Diuretics, Osmotic; D008353:Mannitol; D014747:Vinblastine; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating