In vivo cytochrome P 450 interactions of the newly developed H+/K(+)-ATPase inhibitor pantoprazole (BY 1023/SK&F 96022) compared to other antiulcer drugs.
Almost 10% of adverse drug reactions observed in clinical patients are due to interactions of two or more therapeutic agents (18). The aim of the present study was to investigate in vivo interactions of the H2-blocker cimetidine and three newly developed H+/K(+)-ATPase inhibitors, omeprazole, lansoprazole and pantoprazole (BY 1023/SK&F 96022) with cytochrome P 450 in rats. Because diazepam is a drug used very often as comedication in ulcer patients, the duration of the effects of diazepam on muscle coordination were used to evaluate the drug interactions on metabolic enzymes. The present data indicate a clear rank order of the antiulcer drugs' potency for interaction with diazepam: 1) lansoprazole with a 50% prolongation of diazepam effect at 170 mumol/kg, 2) cimetidine and omeprazole at 281 and 288 mumol/kg, respectively and 3) pantoprazole at greater than 1000 mumol/kg. Because the three H+/K(+)-ATPase inhibitors are approximately equipotent with respect to inhibition of gastric acid secretion, it can be concluded that pantoprazole is superior to omeprazole and lansoprazole when unwanted adverse effects with drug metabolizing enzymes are considered. This may be an advantage in clinical use of the drug.
Hanauer
G
G
Department of Pharmacology, Byk Gulden Pharmaceuticals, Konstanz, Germany.
Graf
U
U
Meissner
T
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole / Q000031:analogs & derivatives; D000077402:Pantoprazole; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013454:Sulfoxides / Q000494:pharmacology*
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D001562:Benzimidazoles; D013454:Sulfoxides; D003577:Cytochrome P-450 Enzyme System; D000077402:Pantoprazole; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole; D003975:Diazepam