Inhibition of P-glycoprotein transport function by grapefruit juice psoralen

Purpose. The grapefruit juice component bergamottin is known to inactivate cytochrome P450 3A4, with grapefruit juice consumption causing increased ab sorption and enhanced oral bioavailability of many cytochrome P450 3A4 subs trates. Many of these substrates are also recognized by the efflux transpor ter P-glycoprotein. The gene product of MDR1 (multidrug resistance transpor ter), P-glycoprotein also confers protection against xenobiotics. Methods. Using a whole cell assay in which the retention of a marker substr ate is evaluated and quantified, we studied the ability of grape fruit juic e components to inhibit the function of this transporter. Results. Ina cell line presenting an overexpressed amount of the human tran sporter, the enzyme exhibited a 40 muM IC50 for inhibition by bergamottin. Additionally, using the ATP-hydrolysis assay, we showed that bergamottin in creases P-gp-mediated ATP hydrolysis by approximately 2.3 fold with a K-m o f 8 muM. The concentration for this interaction is similar to that for CYP3 A4 inactivation. Conclusions. These results suggest that observed grapefruit juice drug phar macokinetic clinical interactions may be due to P-gp inhibition rather than or in addition to CYP3A4 inhibition. Inhibition of P-gp bvcitrus psoralens could present ways both to enhance bioavailability of therapies without in creasing the dose and to diminish drug resistance in refractory cells.