BY-1023-SK-AND-F-96022-INN PANTOPRAZOLE, A NOVEL GASTRIC PROTON PUMP INHIBITOR, POTENTLY INHIBITS ACID-SECRETION BUT LACKS RELEVANT CYTOCHROME-P450 INTERACTIONS

Abstract

The novel H+/K+-adenosine triphosphatase inhibitor (gastric proton pump inhibitor), BY 1023/SK&F 96022, was found to be more potent than omeprazole in some rat models and slightly less potent in a dog model. Overall, both compounds are of a similar potency and efficacy. BY 1023/SK&F 96022 exhibited a somewhat longer duration of the antisecretory action than omeprazole in the Ghosh-Schild rat. In the modified Shay rat, on the basis of equieffective doses in terms of the initial effect, both compounds had a comparable duration of action. However, the p.o./i.v. dose ratio upon acute administration was larger for omeprazole, possibly reflecting its lower stability in the acidic environment of the secreting stomach, compared to BY 1023/SK&F 96022. As in vivo, both compounds were equipotent to inhibit acid production in rabbit isolated fundic glands. However, omeprazole interacted with the 7-ethoxycoumarin dealkylase in vitro with high affinity (Ki = 38.5 .mu.mol/l), in contrast to BY 1023/SK&F 96022 (Ki = 135 .mu.mol/l). Compared to omeprazole, BY 1023/SK&F 96022 also showed less interaction with the cytochrome P450 enzyme hydroxylating Ionazolac. Moreover, this difference between the two compounds was also found in the rat in vivo with respect to their interaction with diazepam. Thus, both compounds displayed a comparable antisecretory potency in vivo and vitro but showed a different interference with cytochrome P450 in favor of less interaction by BY 1023/SK&F 96022.