The Effect of the Interaction between Proton Pump Inhibitors (PPI) and Tyrosine Kinase Inhibitors (Imatinib, Nilotinib and Dasatinib).

Abstract

Background: Proton Pump Inhibitors (PPI) (omeprazole, lansoprazole and pantoprazole) are widely used for the treatment of the gastro-oesophageal reflux disease, as well as other acid- related disorders. All PPI act by covalent binding to the proton pump of the gastric parietal cell and inhibition of the H+, K+ -adenosine triphosphatase [ATPase]. It is known that imatinib mesylate enters the cells through an active pump called hOCT-1. We therefore investigated whether proton pump inhibitors (PPI) could affect OCT-1 function thereby modifying the sensitivity of CML cells to Imatinib and other Tyrosine Kinase Inhibitors (TKI) such as Nilotinib and Dasatinib.Methods: We pretreated K562 cell line for 2 hours with increasing dose of omeprazole (5, 50, and 100 mM), lansoprazole (5, 50, and 100 mM) and pantoprazole (9, 50, and 100 mM). Imatinib (1mM), Dasatinib (5 nM), Nilotinib (0,1 mM) were added and their cytotoxicity was evaluated after 24 hours of incubation using cell death assays (Trypan Blue). As a control the cells were pretreated with ranitidine, an histamine H(2)- receptor blocker, but not proton pump inhibitors.Results: (Table1). Imatinib induced citotoxicity was significantly reduced when cells were pre-treated with 100 μM-omeprazole, 50 and 100 μM-pantoprazole, 50 and 100 μM-lansoprazole. Dasatinib induced cytotoxicity was only slightly decreased at the different doses of PPI, while nilotinib induced cytotoxicity was significantly increased by the highest doses of PPI.Conclusion: Our data provide evidence that proton pump inhibitors might interfere with TKIs activity. The reduction of imatinib cytotoxicity could be due to PPI interaction with OCT-1 that is the active transporter of imatinib. On the contrary, the increase of nilotinib cytotoxicity could be due to PPI inhibition of the efflux pumps such as ABCB1. Similar data (except for dasatinib) have already been reported at 2007 EHA meeting (White, #907) but using very high dose of PPI (> 200 μM). We here demonstrate that this phenomenon starts at low-intermediate concentration of PPI (that are closer to those achievable in vivo after standard dose administration). These interactions may also modify the toxic profile of the TKI and should be kept in mind in clinical practice.Table IImatinib induced citotoxicity47,5%at different concentration PPI (μM):5950100omeprazole47%45%33,8%p value0,70,54<0,0005pantoprazole46,4%28%21,5%p value0,670,0005<0,0005lansoprazole45%35,9%33,8%p value0,260,005<0,0005Dasatinib induced citotoxicity29%at different concentration PPI (μM):5950100omeprazole26%27%27%p value0,010,110,11pantoprazole28,9%27%20,2%p value110,030,005lansoprazole27%24%22,3%p value0,170,0090,0017Nilotinib induced citotoxicity27%at different concentration PPI (μM):5950100omeprazole27%30,5%40,4%p value0,80,09<0,0005pantoprazole25,5%30,3%25,5%p value0,470,0010,01lansoprazole29%34,2%37,9%p value0,490,02<0,0005