Mechanisms of acid release in isolated gas gland cells of the European eel Anguilla anguilla. Interphenotype differences in disposition and effect on gastrin levels of omeprazole--suitability of omeprazole as a probe for CYP2C19. Hydrogen ion concentration in the mucus layer on top of acid-stimulated and -inhibited rat gastric mucosa. Rx drugs

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Am J Physiol. 1995 Oct;269(4 Pt 2):R793-9.
Mechanisms of acid release in isolated gas gland cells of the European eel Anguilla anguilla.

Pelster B.

Institut fur Physiologie, Ruhr-Universitat Bochum, Germany.

Mechanisms of acid production and of acid release have been analyzed in isolated gas gland cells of the eel swimbladder using a cytosensor microphysiometer. Incubation of isolated cells with oxamic acid caused a dose-dependent decrease in the rate of proton release. At the highest oxamic acid concentration used (20 mmol/l), proton release was reduced by approximately 40%; incubation with sodium fluoride (10 mmol/l) or removal of glucose from the extracellular medium caused 60 and 80% reduction, respectively. NaCN had little effect on proton secretion. Proton release of isolated gas gland cells was largely dependent on the extracellular sodium concentration, and this sodium effect was in part inhibitable by amiloride. A 15-20% reduction in the rate of proton secretion was observed in the presence of 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, an inhibitor of anion exchange. Inhibition of mammalian H(+)-K(+)-adenosinetriphosphatase with omeprazole had no effect, whereas bafilomycin, an inhibitor of vesicular H(+)-adenosinetriphosphatase, induced a 25% reduction in proton secretion. Ethoxzolamide, a membrane-permeable inhibitor of carbonic anhydrase, caused a 60% reduction in proton secretion (inhibition constant = 54.4 nmol/l). Prontosil-dextran, a membrane-impermeable sulfonamide, also reduced the proton release, thus indicating the presence of a membrane-bound carbonic anhydrase facing the extracellular space.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7485595&dopt=Abstract

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Br J Clin Pharmacol. 1995 May;39(5):511-8.
Interphenotype differences in disposition and effect on gastrin levels of omeprazole--suitability of omeprazole as a probe for CYP2C19.

Chang M, Tybring G, Dahl ML, Gotharson E, Sagar M, Seensalu R, Bertilsson L.

Department of Clinical Pharmacology, Karolinska Institute, Huddinge University Hospital, Sweden.

1. Fourteen healthy Swedish Caucasian subjects were given 20 mg of omeprazole orally each morning for 8 days. The subjects included five poor metabolisers (PM) of S-mephenytoin, four heterozygous extensive metabolisers (hetEM) and five subjects with a very rapid metabolism (rapidEM). 2. After the first dose, the relative mean areas under the plasma concentration vs time curve (AUC) of omeprazole in rapidEM, hetEM and PM were 1:3.7:20 (all different, P < 0.001). A similar relation was seen in the AUC(0,10 h) of the sulphone metabolite (1:3:12). Concentrations of hydroxyomeprazole were higher in EM than in PM confirming that the hydroxy, but not the sulphone metabolite, is formed by the S-mephenytoin hydroxylase (CYP2C19). After 8 days of treatment, the differences between groups were similar. 3. After both the first and the eighth doses, the omeprazole/hydroxyomeprazole plasma concentration ratio, determined 3 h after drug intake, correlated with the mephenytoin S/R ratio (rs = 0.94; P < 0.001; n = 14) suggesting that omeprazole might be used to phenotype for CYP2C19. 4. After the first dose of omeprazole, there was no difference in the AUC(0,10 h) of plasma gastrin between the three groups. From the first to the eighth dose, the AUC(0,10) of gastrin increased significantly in both hetEM and PM, while there was no change in the rapidEM. After the eighth dose, the AUC(0,10) of gastrin correlated significantly with the AUC of omeprazole in plasma (rs = 0.79; P < 0.01; n = 13).

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7669487&dopt=Abstract

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Gastroenterology. 1994 Jul;107(1):180-8.
Hydrogen ion concentration in the mucus layer on top of acid-stimulated and -inhibited rat gastric mucosa.

Schade C, Flemstrom G, Holm L.

Department of Physiology and Medical Biophysics, Uppsala University Biomedical Center, Sweden.

BACKGROUND/AIMS: The gastric mucosa is covered by a continuous layer of bicarbonate-containing mucus gel; the question arises how acid, formed in the gastric glands, moves into the lumen. METHODS: The pH in the gastric mucus gel and gel thickness were measured in anesthetized rats with pH-sensitive microelectrodes (tip diameter, 1-5 microns). RESULTS: During pentagastrin (40 micrograms.kg-1.h-1) stimulation of acid secretion, the pH was higher in the gel than in the lumen (pH 2) up to a distance of 115 +/- 18 microns from the epithelial surface and maximal (pH 7.2 +/- 0.1) at the surface. A similar pH gradient was recorded at luminal pH 3. After omeprazole (10 mumol/kg) inhibition of endogenous acid secretion and with exogenous acid in the lumen, the pH profile was broader: 204 +/- 26 microns at luminal pH 2 and 231 +/- 63 microns at luminal pH 3. In contrast, the pH at the epithelial surface was lower (pH 6.8-6.9). The gel thickness (200-300 microns) was similar in all groups. CONCLUSIONS: The significantly higher surface pH in acid-secreting stomachs probably reflects better availability of interstitial mucosal bicarbonate. Bulk transport of secreted acid in channels created by the gland luminal hydrostatic pressure may additionally act to limit acidification of the mucus gel.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8020660&dopt=Abstract

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