Grapefruit juice activates P-glycoprotein-mediated drug transport

Purpose. Grapefruit juice (GJ) is known to increase the oral bioavailabilit y of many CYP3A-substrates by inhibiting intestinal phase-1 metabolism. How ever, the magnitude of AUC increase is often insignificant and highly varia ble. 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-a nd/or P-gp substrates (Vinblastine, Cyclosporine, Digoxin, Fexofenadine, Lo sartan) or that are (ii) primary CYP3A-substrates (Felodipine, Nifedipine) was evaluated across MDCK-MDRI cell monolayers with or without GJ, verifyin g 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, t he resulting net efflux (B-A/A-B) was in all cases significantly greater wi th 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 effec t 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-inhib itory effects of GJ.