Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein

Proton pump inhibitors are a class of drugs which are widely prescribed for acid-related diseases. They are primarily metabolized by CYP2C19 and CYP3A 4. It is unknown so far whether proton pump inhibitors are also substrates of the ATP-dependent efflux transporter P-glycoprotein. Moreover, it is not established whether proton pump inhibitors are also inhibitors of P-glycop rotein function. The aim of our study was therefore to characterize omepraz ole, lansoprazole and pantoprazole as P-glycoprotein substrates and inhibit ors. Polarized transport of these compounds was assessed in P-glycoprotein-expre ssing Caco-2 and L-MDR1 cells. Inhibition of P-glycoprotein-mediated transp ort was determined using the cyclosporine analogue PSC-833 (valspodar) as P -glycoprotein inhibitor. Inhibition of efflux transport by omeprazole, lans oprazole and pantoprazole was assessed using digoxin as P-glycoprotein subs trate. At concentrations of 5 muM, basal-to-apical transport of omeprazole, lansop razole and pantoprazole was greater than apical-to-basal transport in Caco- 2 and L-MDR1 cells. Addition of PSC-833 (1 muM) showed a clear effect only for lansoprazole, suggesting that other transporters contribute to omeprazo le and pantoprazole cellular translocation. Furthermore, all of the tested compounds inhibited digoxin transport with IC50 values of 17.7, 17.9 and 62 .8 muM for omeprazole, pantoprazole and lansoprazole, respectively. In summ ary, our data provide evidence that proton pump inhibitors are substrates a nd inhibitors of P-glycoprotein. These findings might explain some of the d rug interactions with proton pump inhibitors observed in vivo.