Gastric pH value

The percentage of time the gastric pH values remained above 4 by day 8 was 60.3% and 50.4%, respectively. However, this was only significant on the first day of therapy." Another smdy showed rabeprazole 20 mg and 40 mg increased mean gastric pH to 4.2 and 4.7, respectively. The percentage of time the esophageal pH was <4 was decreased and fewer reflux episodes were noted with both doses." ... 

A study in 10 healthy subjects found that 10 mL of an aluminium/magnesium hydroxide antacid (Maalox) reduced the bioavailability of cefpodoxime proxetil by about 40%. This was considered to be due to reduced dissolution at increased gastric pH values. These results confirm the findings of a previous study with sodium bicarbonate and aluminium hydroxide. It has been recommended that cefpodoxime is given at least 2 hours after antacids. ... 

The reduction in the bioavailability of some of the cephalosporins is thought to be due to reduced dissolution at increased gastric pH values. ... 

As for bases, only the weakest are absorbed to any appreciable extent at normal gastric pH, but their absorption can be increased substantially by neutralizing the stomach contents. The quaternary cations, however, which are charged at all pH values, are not absorbed at either pH. 

Figure 6 Typical solubility behavior for a poorly soluble weak base as a function of pH. The intrinsic solubility is 0.4 pg/mL. At pH values typical of the small intestine, solubility is minimally better than the intrinsic solubility (solubility of the free base form) but at gastric pH ( 2) the solubility is about 16 mg/mL.

The reversibility of lactone hydrolysis in HMG-CoA reductase inhibitors has been demonstrated at gastric pH and temperature (pH 2.0, 37°) [186], For the prodrug lovastatin (8.148), reversible lactone hydrolysis to its active hydroxy acid (8.149) occurred with a f1/2 value of ca. 1 h and an equilibrium constant close to one. Similar results were obtained for some closely related compounds. In contrast, this reversible hydrolysis was much slower under the nearly neutral pH conditions of the intestine. 

Figure 6.2 Two major surgical models of BO and OA, oesophagojejunostomy with gastric preservation (A) and oesophagojejunostomy with total gastrectomy (B). Figure 2A shows intra-luminal pH values in the animals one week after esophagojejunostomy and preservation of the stomach (adapted from Fein al.).

Most substances are not readily absorbed in the mouth or esophagus one of several exceptions is nitroglycerin, which is administered for certain heart disfunctions and absorbed if left in contact with oral tissue. The stomach is the first part of the gastrointestinal tract where substantial absorption and translocation to other parts of the body may take place. The stomach is unique because of its high content of HC1 and consequent low pH (about 1.0). Therefore, some substances that are ionic at pH values near 7 and above are neutral in the stomach and readily traverse the stomach walls. In some cases, absorption is affected by stomach contents other than HC1. These include food particles, gastric mucin, gastric lipase, and pepsin. 

The effect of gastric HVK -ATPase inhibitors on enzyme activity (ATP cleavage) can be studied in vitro with partly purified HVK -ATPase preparations [27]. This assay has been used more effectively to study the mechanism of action of H /K -ATPase inhibitors in detail than to study the structure-activity relationship of such inhibitors [28]. Since HVK -ATPase inhibitors of the omeprazole-type need acid activation and the enzyme assay should be performed at neutral pH values, a pre-incubation period at the lowest possible pH of about 6 was used to initiate the acidic conversion of the test compound into its active principle. This reflects more the chemical instability of the test compound at neutral pH values than its effect during conditions of much higher acidity within the secretory cannaliculus of the parietal cell during acid secretion. Many chemically labile inhibitors are therefore very active in this test system. However, they do not cause an inhibition in more complex test systems and, therefore, are without any practical usefulness [28]. 

The structure-activity relationship of HVK -ATPase inhibitors of the omeprazole type is based on the balance between chemical stability at neutral pH values and acid-induced conversion into the active sulphenamide. Derivatives, which are too unstable at neutral pH, are very active in the test assay of partly purified HVK" -ATPase. This assay has been performed at pH 7.4 after preincubation at pH 6 of the enzyme protein with the derivative to be tested. The high activity was therefore the result of the conversion of the derivative in solutions of neutral pH values and this does not reflect the situation of high acidity within the secretory compartment of the parietal cell [28]. The derivatives which are very unstable at neutral pH do not inhibit gastric acid secretion in vivo because their transformation had already occurred prior to the active principle reaching the target enzyme. Chemically very stable derivatives do not show any inhibitory effect either in vitro or in vivo. 

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