Grapefruit Juice Activates P-Glycoprotein-Mediated Drug Transport
Andrea Soldner,' Uwe Christians,' Miki Susanto,' Vincent J. Wacher,' Jeffrey A. Silverman,' and Leslie Z. Benet l,3 Purpose. 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-MDR I 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. I 1. 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, Christians U, Susanto M et al.
Grapefruit Juice Activates P-Glycoprotein Mediated Drug Transport.
Pharm Res 1999; 16: 478-85.