The H+, K(+)-ATPase inhibitor pantoprazole (BY1023/SK&F96022) interacts less with cytochrome P450 than omeprazole and lansoprazole.
The gastric acid antisecretory compound omeprazole (5-methoxy-2-((4-methoxy- 3,5-dimethyl-2-pyridinylmethyl)-sulphinyl)-1H-benzimidazole), a member of the new class of H+, K(+)-ATPase inhibitors, is known to interact with the metabolism of other drugs in vitro and in vivo. In this study, two other substituted benzimidazoles, pantoprazole (5-difluoromethoxy-2-((3,4-di-methoxy-2-pyridinylmethyl)-s ulp hinyl)-1H- benzimidazole) and lansoprazole (2-((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinylmethyl)- sulphinyl)-1H-benzimidazole) are compared for their ability to inhibit cytochrome P450 dependent biotransformation in vitro with regard to three representative reactions: O-dealkylation of 7-ethoxycoumarin (EC), N-demethylation of ethylmorphine (EM) and hydroxylation of lonazolac (Lona). These reactions can be seen in microsomes from phenobarbital pretreated rats representing the cytochrome P450IIB1 subfamily. As shown in presence of known inhibitors of cytochrome P450, e.g. SK&F 525A, metyrapone, chlorpromazine and nitrendipine, different enzymes seem to be responsible for these three indicator reactions of the cytochrome P450IIB1 complex. These reactions are inhibited to a different extent by the three H+, K(+)-ATPase inhibitors. Pantoprazole shows the lowest inhibitory activity versus the three reactions (Ki, mumol/L): EC, 138; EM, 104; Lona, 128. A greater effect is observed with omeprazole: EC, 38; EM, 68; Lona, 20. Lansoprazole exceeds omeprazole in inhibiting the three cytochrome P450 dependent enzymes: EC, 17; EM, 34; Lona, 8. In microsomes from untreated rats with the predominant cytochrome P450IIA1 subfamily as well as in microsomes from isopropanol treated rats (induction of cytochrome P450IIE1) which catalyse only lonazolac hydroxylation to a detectable amount, the latter reaction was inhibited by pantoprazole with a somewhat lower Ki of 77 whereas the values for omeprazole and lansoprazole remained unchanged in comparison to those found in microsomes from phenobarbital pretreated rats. The biotransformation rate of the substituted benzimidazoles themselves in microsomes from control and induced rats is lowest for pantoprazole followed by lansoprazole and omeprazole.
Simon
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WA
Byk Gulden Pharmazeutika, Konstanz, Germany.
Büdingen
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C
Fahr
S
S
Kinder
B
B
Koske
M
M
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D015660:7-Alkoxycoumarin O-Dealkylase / Q000037:antagonists & inhibitors; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D005037:Ethylmorphine-N-Demethylase / Q000037:antagonists & inhibitors; D005260:Female; D017506:H(+)-K(+)-Exchanging ATPase; D007700:Kinetics; D064747:Lansoprazole; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077402:Pantoprazole; D011720:Pyrazoles / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013454:Sulfoxides / Q000494:pharmacology*
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D011720:Pyrazoles; D013454:Sulfoxides; D064747:Lansoprazole; C017472:lonazolac; D000077402:Pantoprazole; D015660:7-Alkoxycoumarin O-Dealkylase; D005037:Ethylmorphine-N-Demethylase; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole