Effects of the enantiomers of lansoprazole (AG-1749) on (H+ + K+)-ATPase activity in canine gastric microsomes and acid formation in isolated canine parietal cells

Nagaya, Hideaki; Inatomi, Nobuhiro; Nohara, Akira; Satoh, Hiroshi

doi:10.1016/0006-2952(91)90584-r

Cited by 36 publications

(26 citation statements)

References 8 publications

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“…[1][2][3][4][5] Lansoprazole is extensively metabolized in the liver to 5-hydroxylansoprazole and lansoprazole sulfone by CYP2C19 and CYP3A4, respectively (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…Both enantiomers of these PPIs have been shown to possess equal potency in vitro. 2) Generally, the pharmacokinetics of enantiomers of chiral compounds diŠer in the human body. In omeprazole, which is one class of PPIs, the plasma concentrations of (S )-omeprazole are higher and less in‰uenced by CYP2C19 genetic polymorphisms compared to those of ( R)-omeprazole or racemic omeprazole.…”

Section: Introductionmentioning

confidence: 99%

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Enantioselective Disposition of Lansoprazole and Rabeprazole in Human Plasma

Miura

2006

YAKUGAKU ZASSHI

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Lansoprazole is extensively metabolized by CYP2C19 and CYP3A4 in the liver, whereas rabeprazole is primarily converted non-enzymatically to rabeprazole-thioether, with only some being oxidized by CYP2C19 and CYP3A4. Lansoprazole and rabeprazole possess asymmetric sulfur in their chemical structure and have typically been used clinically as a racemic mixture. This article reviews the pharmacokinetic diŠerences between enantiomers of lansoprazole and rabeprazole in relation to the CYP2C19 genotypes. In our studies in healthy Japanese subjects, the magnitude of contribution of each lansoprazole enantiomer for CYP2C19 was greater than that for CYP3A4. CYP2C19 in‰uenced the disposition of (S )-lansoprazole to a greater extent than the ( R)-enantiomer. The R/S ratios for the AUC of lansoprazole in CYP2C19 homEMs, hetEMs and PMs was 12.7, 8.5 and 5.8, respectively. On the other hand, (R)-rabeprazole disposition was in‰uenced to a greater degree by CYP2C19 genetic polymorphisms than (S )-rabeprazole. However, the R/S ratios for the AUC of rabeprazole in CYP2C19 homEMs, hetEMs and PMs was only 1.8, 2.2 and 2.4, respectively, suggesting a lesser eŠect of CYP2C19 polymorphisms on the stereoselective disposition of rabeprazole compared to lansoprazole. Such a diŠerence in the AUC between rabeprazole enantiomers is likely to be dependent on stereoselectivity in the CYP3A4-mediated metabolic conversion from rabeprazole-thioether to rabeprazole. Both enantiomers of these PPIs have been reported to possess equal potency. Therefore, particularly with lansoprazole, the use of ( R)-lansoprazole alone would be highly desirable for use in clinical applications.

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“…[1][2][3][4][5] Lansoprazole is extensively metabolized in the liver to 5-hydroxylansoprazole and lansoprazole sulfone by CYP2C19 and CYP3A4, respectively (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enantioselective Disposition of Lansoprazole and Rabeprazole in Human Plasma

Miura

2006

YAKUGAKU ZASSHI

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“…Lansoprazole is a proton pump inhibitor (PPI 1 ) that suppresses gastric acid secretion via interaction with H ϩ /K ϩ -ATPase in gastric parietal cells (Nagaya et al, 1991). This agent is frequently prescribed to treat acid-related disorders, such as gastric and duodenal ulcers, Zollinger-Ellison syndrome, and other hypersecretory diseases (Barradell et al, 1992).…”

mentioning

confidence: 99%

Stereoselective Metabolism of Lansoprazole by Human Liver Cytochrome P450 Enzymes

Kim

Park³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The stereoselective metabolism of lansoprazole enantiomers was evaluated by incubation of human liver microsomes and cDNAexpressed cytochrome P450 (P450) enzymes to understand and predict their stereoselective disposition in humans in vivo. The intrinsic clearances (Cl int ) of the formation of both hydroxy and sulfone metabolites from S-lansoprazole were 4.9-and 2.4-fold higher than those from the R-form, respectively. The sums of formation Cl int of both metabolites were 13.5 and 57.3 l/min/mg protein for R-and S-lansoprazole, respectively, suggesting that S-lansoprazole would be cleared more rapidly than the R-form. The P450 isoform selective inhibition study in liver microsomes, and the incubation study of cDNA-expressed enzymes, demonstrated that the stereoselective sulfoxidation is mediated by CYP3A4 and that the hydroxylation is mediated by CYP2C9 and CYP3A4 as well as by CYP2C19. Total Cl int values of hydroxy and sulfone metabolite formation catalyzed by all these P450 enzymes were consistently higher for S-lansoprazole than for the R-form. The CYP3A4 produced the greatest difference of Cl int between Sand R-enantiomers, mainly due to a difference of sulfoxidation metabolism (Cl int 76.5 versus 10.8 l/min/nmol of P450, respectively), whereas CYP2C19-catalyzed hydroxylation resulted in a minor difference of Cl int between S-and R-enantiomers (179.6 versus 143.3 l/min/nmol of P450, respectively). However, the affinity of CYP2C19 on hydroxylation was 5.7-fold higher for S-enantiomer than for the R-form (K m 2.3 versus 13.1 M), suggesting that the role of CYP2C19 on stereoselective hydroxylation would be more prominent at concentrations around the usual therapeutic level. These findings suggest that both CYP2C19 and CYP3A4 are major enzymes contributing to the stereoselective disposition of lansoprazole, but stereoselective hydroxylation of lansoprazole enantiomers is mainly influenced by CYP2C19, especially at the usual therapeutic doses.

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“…Omeprazole is highly selective for the proton pump and undergoes catalysed conversion into an active form within the acid forming space. The active inhibitors react with SH (thiol) group of the proton pump, resulting in inhibition of acid formation [22].…”

Section: Discussionmentioning

confidence: 99%

Leaves Extract of Muntingia Calabura Protects Against Gastric Ulcer Induced by Ethanol in Sprague-Dawley Rats

Ibrahim¹

2012

Clinic Experiment Pharmacol

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Aim: Muntingia calabura is a medicinal plant used popularly known in Malaysia against various diseases including peptic ulcer. This study was performed to evaluate the gastroprotective effect of ethanolic extracts of Muntingia calabura Leaf Extract (MCELE) against ethanol-induced gastric mucosal injury in experimental rats. Methods:The rats were divided into four groups respectively pre-treated orally with Carboxymethyl Cellulose (CMC) solution (ulcer control groups), omeprazole 20 mg/kg (reference group), 250 and 500 mg/kg of MCELE (experimental groups) one hour before oral administration of absolute ethanol to generate gastric mucosal damage. After an additional hour, the rats were sacrificed and the ulcerated areas of the gastric walls were determined. Results:The ulcer control group exhibited severe mucosal injury, whereas groups pre-treated with the MCELE exhibited significant protection of gastric mucosa. These findings were also confirmed by histology of the gastric wall. Significant increases in gastric mucus production and decrease in acidity of gastric content were observed in the treated groups with MCELE compare to ulcer control group. Conclusions:The treatment with MCLELE prior to absolute alcohol has significantly protect gastric mucosa as ascertained by significant reduction of ulcer area, increases in gastric mucus production, decrease the acidity of gastric content and histology by comparatively decreases gastric mucosal injury, reduction of oedema and leukocyte infiltration of submucosal layer. MCELE was able to decrease the acidity and increase the mucosal defence in the gastric area, thereby justifying its use as an antiulcerogenic agent.

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Effects of the enantiomers of lansoprazole (AG-1749) on (H+ + K+)-ATPase activity in canine gastric microsomes and acid formation in isolated canine parietal cells

Cited by 36 publications

References 8 publications

Enantioselective Disposition of Lansoprazole and Rabeprazole in Human Plasma

Enantioselective Disposition of Lansoprazole and Rabeprazole in Human Plasma

Stereoselective Metabolism of Lansoprazole by Human Liver Cytochrome P450 Enzymes

Leaves Extract of Muntingia Calabura Protects Against Gastric Ulcer Induced by Ethanol in Sprague-Dawley Rats

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