An evaluation of the cytochrome P450 induction potential of pantoprazole in primary human hepatocytes.
Primary human hepatocytes contain a full complement of human drug-metabolizing enzymes and therefore represent a relevant experimental system for the evaluation of pharmacokinetic drug-drug interaction potential in human. In this study, the cytochrome P450 (CYP) induction potential of pantoprazole (PAN) was evaluated and compared to two other proton pump inhibitors (PPIs), omeprazole (OM) and lansoprazole (LAN). Primary human hepatocytes from three donors were studied. The hepatocytes were cultured for 3 days, followed by treatment for 3 days with the PPIs at 2, 5 and 10 microM. Two other known CYP inducers, 3-methylcholanthrene at 1 microM and rifampin at 50 microM, were also evaluated. Induction potentials of these chemicals for CYP1A and CYP3A were evaluated by isozyme activity and isozyme content. 7-Ethoxyresorufin-O-deethylase and testosterone 6beta-hydroxylase activities were used as endpoints for CYP1A and CYP3A, respectively. Isozyme protein contents of CYP1A and CYP3A were evaluated via Western blotting. The results showed that for CYP1A induction, the rank ordering in induction potential was consistently OM > LAN > PAN. CYP3A induction by the PPI's were observed in two of the three hepatocyte cultures, with no apparent differences in induction potency for the three compounds. Our results on CYP1A induction suggest that PAN has a lower drug-drug interaction potential than OM and LAN.
Masubuchi
N
N
Drug Metabolism and Analytical Chemistry Research Laboratory, Daiichi Pharmaceutical, Tokyo, Japan.
Li
A P
AP
Okazaki
O
O
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000368:Aged; D001562:Benzimidazoles / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D064747:Lansoprazole; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008875:Middle Aged; D009853:Omeprazole / Q000031:analogs & derivatives / Q000494:pharmacology; D000077402:Pantoprazole; D012293:Rifampin / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D013454:Sulfoxides / Q000494:pharmacology*
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D013454:Sulfoxides; D064747:Lansoprazole; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D000077402:Pantoprazole; D013250:Steroid Hydroxylases; D019363:Cytochrome P-450 CYP1A1; C022657:steroid hormone 6-beta-hydroxylase; D009853:Omeprazole; D012293:Rifampin