Prevacid
A comparative study on the activity of lansoprazole, omeprazole and PD-136450 on acidified ethanol- and indomethacin-induced gastric lesions in the rat.

Chandranath SI, Bastaki SM, Singh J.

Department of Pharmacology, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.

1. The proton pump inhibitors lansoprazole (LP) and omeprazole (OP) and the cholecystokinin (CCK)-receptor antagonist PD-136450 (PD) provide a broad spectrum of activities in their ability to inhibit gastric acid secretion and protect the stomach against ulcerogens. In the present study, we investigated the protective effects of these compounds against gastric ulcers induced by acidified ethanol (AE) and indomethacin. 2. Both AE (60% ethanol in 150 mmol/L HCl, 1 mL/rat) and indomethacin (30 mg/kg) produced gastric haemorrhagic lesions in the rat 1 and 6 h after oral administration, respectively. 3. The gastric mucosal protective effects of LP (1-20 mg/kg), OP (0.5-10 mg/kg) and PD (1-20 mg/kg), administered either orally or subcutaneously (s.c.) 30 min before the administration of AE or indomethacin, were dose dependent against both models of ulcer induction. 4. To determine whether the cytoprotective effect of LP, OP and PD (each 10 mg/kg) was mediated by endogenous prostaglandins (PG), indomethacin (10 mg/kg, s.c.) was administered 15 min before AE to inhibit prostanoids biosynthesis. Indomethacin reduced the cytoprotective effects of OP, but not LP, administered either orally or s.c. Indomethacin reduced the cytoprotective effect of PD administered orally, although the effect was much less significant than when PD was administered s.c. The results exclude the role of PG in mediating the protective effects of LP, whereas the possibility exists for PG to have a role in mediating the protective effects of OP and PD. 5. To investigate the possible involvement of endogenous nitric oxide (NO) in the cytoprotective action of LP, OP and PD, we treated rats with a selective inhibitor of NO synthesis, namely NG-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg, s.c.). Administration of L-NAME 15 min prior to LP, OP or PD (each 10 mg/kg) orally or s.c. and challenge with AE or indomethacin did not significantly increase the degree of the ulcer index and L-NAME was not able to antagonize the protective effects of LP, OP and PD, thus excluding the role of NO in mediating the protective effects of these drugs. However, the effects of PD in reducing the indomethacin-induced ulcer index were less significant in the presence than the absence of L-NAME (P < 0.05 vs P < 0.001, respectively), suggesting a role for NO. 6. In conclusion, the results of the present study suggest that LP and OP are equally effective against AE- as well as indomethacin-induced gastric ulcers and were more potent than PD in protecting the stomach against ulcer formation. Lansoprazole, OP and PD bring about their cytoprotective action through the reduction of acid secretion and some other unknown mechanisms. However, OP and PD may exert their cytoprotective action through PG and NO pathways.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11906479&dopt=Abstract lansoprazole Prevacid



Prevacid
Pharmacokinetic differences between lansoprazole enantiomers and contribution of cytochrome P450 isoforms to enantioselective metabolism of lansoprazole in dogs.

Masa K, Hamada A, Arimori K, Fujii J, Nakano M.

Department of Pharmacy, Kumamoto University Hospital, Japan.

The purpose of this study was to evaluate the pharmacokinetics of lansoprazole enantiomers and contribution of cytochrome P450 enzymes to enantioselective metabolism in dogs. The mean Cmax and area under the curve (AUC) values of (+)-lansoprazole were 4-5 times greater than those of (-)-lansoprazole following oral administration of 30-mg racemic lansoprazole to dogs. The CLtot/F values of (+)-lansoprazole were significantly smaller than those of (-)-lansoprazole (p<0.05). The mean unbound fraction of (-)-lansoprazole was significantly greater than that of the (+)-lansoprazole. The amount of (+)-lansoprazole remaining was significantly greater than that of the (-)-lansoprazole after incubation of racemic lansoprazole in dog liver microsomes. When the effects of ticlopidine or ketoconazole on the metabolism of lansoprazole were studied using dog liver microsomes, ticlopidine significantly inhibited the formation of 5-hydroxylansoprazole, but not another metabolite, lansoprazole sulfone; however ketoconazole significantly inhibited formation of both metabolites. When the amount of (+)- and (-)-enantiomers remaining was measured in the presence and absence of ticlopidine, the amount of (+)-lansoprazole was significantly greater than that of the (-)-lansoprazole. On the other hand, there was no significant difference between the amount of (+)- and (-)-enantiomers remaining in combination with ketoconazole. These results suggest that the enantioselective pharmacokinetics of lansoprazole enantiomers are probably ascribable to their enantioselective protein binding and/or metabolism, and among the cytochrome P450 enzymes, CYP3A contributed to the enantioselective metabolism of lansoprazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11256484&dopt=Abstract lansoprazole Prevacid



Prevacid
Effects of lansoprazole, clarithromycin and pH gradient on uptake of [14C]amoxycillin into rat gastric tissue.

Endo H, Yoshida H, Ohmi N, Higuchi S.

Department of Drug Metabolism, Research Center, Taisho Pharmaceutical Co., Ltd, 403, Yoshino-cho 1-chome, Omiya-shi, Saitama 330-8530, Japan. S14952 ccm.taisho.co.jp

The effect of lansoprazole and clarithromycin on the uptake of [(14)C]amoxycillin into rat gastric tissue was investigated. After oral administration of [(14)C]amoxycillin, the levels of radioactivity in gastrointestinal tissue were two to 15 times higher than those in plasma. The level of radioactivity in glandular stomach was significantly higher when lansoprazole and [(14)C]amoxycillin were administered together. After intravenous administration of [(14)C]amoxycillin, there was less radioactivity in gastric tissue than after oral administration, and co-administration of lansoprazole and clarithromycin had no obvious effect. The gastric emptying rate of [(14)C]amoxycillin was not apparently affected by the co-administration of lansoprazole and clarithromycin. In vitro uptake of [(14)C]amoxycillin into gastric tissue depended on the pH, with uptake at pH 7.4 being four times greater than that at pH 4.0. The apparent synergic effects of lansoprazole are due to enhanced penetration of amoxycillin in gastric mucus and tissue by increasing intragastric pH and play an important role in the eradication of H. pylori.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11266411&dopt=Abstract lansoprazole Prevacid



Prevacid
Electrochemical studies and differential pulse polarographic analysis of lansoprazole in pharmaceuticals.

Yardimci C, Ozaltin N.

Department of Analytical Chemistry, Faculty of Pharmacy, University of Hacettepe, 06100, Sihhiye, Ankara, Turkey.

The electrochemical reduction of lansoprazole was investigated by cyclic voltammetry and direct current and differential pulse polarography. The reduction potential was -1.32 V vs. Ag/AgCl with a dropping mercury electrode in a supporting electrolyte consisting of phosphate buffer (pH 9.0)-tetramethylammonium iodide (4 + 1). The reversibility of the electrode reaction and the type of limiting current were studied. The temperature coefficient and the diffusion constant were determined. A mechanism for the electrode reaction was proposed. A new simple and sensitive differential pulse polarographic method was also developed for the quantification of lansoprazole. A linear calibration graph was obtained in the range 0.04-11.35 micrograms ml-1. The limit of detection was 0.03 microgram ml-1 and the intra- and inter-day precisions were 0.84-2.32 and 0.72-3.09%, respectively. The developed method was applied to six different commercial pharmaceutical capsule preparations containing enteric-coated granules. The relative standard deviations ranged from 1.36 to 2.85%. Recovery studies for the accuracy of the method were performed by adding a synthetic mixture to known amounts of lansoprazole and the mean recovery was 100.45%. The data obtained from commercial preparations were compared with those from a published spectrophotometric method. No difference was found statistically.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11284340&dopt=Abstract lansoprazole Prevacid



Prevacid
Inhibitory activities of lansoprazole against respiration in Helicobacter pylori.

Nagata K, Sone N, Tamura T.

Department of Bacteriology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan. kunagata hyo-med.ac.jp

Lansoprazole and its derivative AG-1789 dose-dependently inhibited cellular respiration by an endogenous substrate and decreased the ATP level in Helicobacter pylori cells. The inhibitory action of lansoprazole and AG-1789 against respiration was specific to substrates such as pyruvate and alpha-ketoglutarate and similar to the inhibitory action of rotenone, which is an inhibitor for the mitochondrial respiratory chain. Growth inhibition by lansoprazole and AG-1789 as well as by rotenone was augmented at high oxygen concentrations under atmospheric conditions. Since the 50% inhibitory concentrations of these compounds for the respiration were close to their MICs for H. pylori growth, the growth inhibition might be due to respiratory inhibition by these compounds.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11302821&dopt=Abstract lansoprazole Prevacid