AN EVALUATION OF THE CYTOCHROME-P450 INDUCTION POTENTIAL OF PANTOPRAZOLE IN PRIMARY HUMAN HEPATOCYTES

Primary human hepatocytes contain a full complement of human drug-meta bolizing enzymes and therefore represent a relevant experimental syste m for the evaluation of pharmacokinetic drug-drug interaction potentia l in human. In this study, the cytochrome P450 (CYP) induction potenti al of pantoprazole (PAN) was evaluated and compared to two other proto n pump inhibitors (PPIs), omeprazole (OM) and lansoprazole (LAN). Prim ary human hepatocytes from three donors were studied. The hepatocytes were cultured for 3 days, followed by treatment for 3 days with the PP Is at 2, 5 and 10 mu M. Two other known CYP inducers, 3-methylcholanth rene at 1 mu M and rifampin at 50 mu M, were also evaluated. Induction potentials of these chemicals for CYP1A and CYP3A were evaluated by i sozyme activity and isozyme content. 7-Ethoxyresorufin-O-deethylase an d testosterone 6 beta-hydroxylase activities were used as endpoints fo r CYP1A and CYP3A, respectively. Isozyme protein contents of CYP1A and CYP3A were evaluated via Western blotting. The results showed that fo r CYP1A induction, the rank ordering in induction potential was consis tently OM > LAN > PAN. CYP3A induction by the PPI's were observed in t wo of the three hepatocyte cultures, with no apparent differences in i nduction potency for the three compounds. Our results on CYP1A inducti on suggest that PAN has a lower drug-drug interaction potential than O M and LAN. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.