Aciphex
Kinetic studies of Helicobacter pylori urease inhibition by a novel proton pump inhibitor, rabeprazole.

Park JB, Imamura L, Kobashi K.

Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Japan.

Urease is an important virulence factor of pathogenicity of gastric Helicobacter pylori. The inhibition of H. pylori urease by the novel proton pump inhibitor, rabeprazole, was investigated kinetically. It was found to act as an irreversible noncompetitive inhibitor of the enzyme. The inhibitory potency of rabeprazole was dependent on the pH of reaction mixture and its Ki values were 0.14 microM (pH 5.0), 0.34 microM (pH 7.0) and 6.10 microM (pH 8.5). Progressive inactivation of urease by rabeprazole initially proceeded according to pseudo-first-order kinetics with respect to the remaining enzymatic activity at pH 7.0 and 37 degrees C, with a second-order rate constant of 0.0017 microM-1 s-1. When the inactivation half-life was plotted versus the reciprocal of the rabeprazole concentration, a straight line was obtained with a slope of -3.12. From an Arrhenius-plot of the temperature-dependence of the inactivation (over the range of 5-37 degrees C), an activation energy of 13.2 kcal/mol was calculated. Recovery of activity was incomplete for H. pylori urease inhibited by rabeprazole, suggesting that the rabeprazole-urease complex is very stable.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8850302&dopt=Abstract rabeprazole Aciphex



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Effects of rabeprazole, a gastric proton pump inhibitor, on biliary and hepatic lysosomal enzymes in rats.

Fujisaki H, Oketani K, Nagakawa J, Takenaka O, Yamanishi Y.

Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.

The effects of rabeprazole (E3810), omeprazole and chloroquine on hepatic lysosomal function were studied. After chloroquine (50 mg/kg), rabeprazole (5 mg/kg) or omeprazole (5 mg/kg) was given intraperitoneally to rats for 6 days, the bile was collected via a bile duct cannula for 5 hr, and hepatic and biliary lysosomal enzyme (N-acetyl-beta-glucosaminidase and beta-galactosidase) activities were measured. The latency (an index for the hepatic lysosomal membrane integrity) was calculated from the N-acetyl-beta-glucosaminidase activity. The biliary constituents and plasma concentrations of lipids were also measured. The administration of chloroquine significantly increased hepatic and biliary lysosomal enzyme activities, but did not affect the lysosomal enzyme latency, hepatic and biliary protein content or bile flow. It significantly decreased the bile acid level. On the other hand, the administration of rabeprazole and omeprazole did not alter the lysosomal enzyme activities, lysosomal enzyme latency, protein content in liver or liver weight. Furthermore, no significant differences were observed in biliary lysosomal enzyme activity, protein content, bile flow, biliary constituents or in the plasma concentrations of lipids between the drug groups (rabeprazole or omeprazole) and the control group. The results of the present study indicate that rabeprazole, like omeprazole, does not influence hepatic lysosomal function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9593221&dopt=Abstract rabeprazole Aciphex



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Cytoprotective effect of rabeprazole against ethanol-induced gastric mucosal damage: possible involvement of nitric oxide.

Watanabe T, Higuchi K, Tominaga K, Fujiwara Y, Arakawa T.

Department of Biosignal Analysis, Osaka City University Medical School, Japan. watanabet med.osaka-cu.ac.jp

The cytoprotective effect of rabeprazole, a new proton pump inhibitor, against ethanol-induced gastric mucosal damage was investigated in rats. Rats received intraperitoneal injections of rabeprazole once only or once daily for 3 days. Subsequently, the rats were given 1 ml of absolute ethanol by oral intubation. Some rats given rabeprazole were treated with N-omega-nitro-L-arginine methyl ester (L-NAME) or indomethacin. Repeated administration of rabeprazole significantly inhibited ethanol-induced gastric mucosal damage, although single administration of this drug did not. Pretreatment with L-NAME abolished the cytoprotective effect of rabeprazole. This inhibitory effect of L-NAME was reversed by L-arginine but not by D-arginine. Pretreatment with indomethacin did not influence the cytoprotective effect of rabeprazole. These results suggest that repeated intraperitoneal administration of rabeprazole has a cytoprotective effect against ethanol-induced gastric mucosal damage and that this effect may be mediated via nitric oxide but not via prostaglandins.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10894554&dopt=Abstract rabeprazole Aciphex