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 absorption and enhanced oral bioavailability of many cytochrome P450 3A4 substrates. Many of these substrates are also recognized by the efflux transporter P-glycoprotein. The gene product of MDR1 (multidrug resistance transporter), P-glycoprotein also confers protection against xenobiotics. Methods. Using a whole cell assay in which the retention of a marker substrate is evaluated and quantified, we studied the ability of grape fruit juice components to inhibit the function of this transporter. Results. Ina cell line presenting an overexpressed amount of the human transporter, the enzyme exhibited a 40 muM IC50 for inhibition by bergamottin. Additionally, using the ATP-hydrolysis assay, we showed that bergamottin increases P-gp-mediated ATP hydrolysis by approximately 2.3 fold with a K-m of 8 muM. The concentration for this interaction is similar to that for CYP3A4 inactivation. Conclusions. These results suggest that observed grapefruit juice drug pharmacokinetic 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 increasing the dose and to diminish drug resistance in refractory cells.