Where is omeprazole absorbed

The PPIs are inactive in their native form and are rapidly metabolized by the liver. Since PPI is an acid-activated prodrug, it is important to keep the PPI plasma level high until the gastric acid secretes. Maintaining high plasma level of the drug is significantly affected by the character of the metabolism.

Metabolism of PPIs is dependent on the cytochrome P system. Omeprazole is a racemic mixture of 2 enantiomers, R-omeprazole and S-omeprazole.

Each enantiomer showed different affinity to the CYP enzyme. Major metabolites of lansoprazole are 5-hydroxy lansoprazole and the sulfone. Similar patterns of metabolism were observed in pantoprazole and rabeprazole.

It is clear that the quantity of PPI bound to the enzyme is directly linked to the inhibition of gastric acid secretion. However, it is very difficult to measure the quantity of PPI binding in vivo, so we need another parameter substituting the quantity of PPI binding. As discussed above, the plasma level of the drug was not linear to the inhibitory activity. It was, however, observed that the gastric antisecretory effect was related to the total dose and AUC, whereas the peak level or the shape of the curve was of minor importance.

However, this relationship is only acceptable up to a certain level such as the ED50 level of dosage. Linear relationship between the inhibitory activity and AUC was not shown at higher dosage of the drug. Though the relationship between AUC and the inhibition was not linear at higher dosage of the drug due to the short half-life of the drug and the limited exposure of the enzyme to the drug, at least AUC showed the efficacy of the drug with good reliability.

Unlike the animal model, the measurement of inhibition of acid output in human is not easy, so measuring intragastric pH is used to present the inhibition due to drug activity. Actually, control of the intragastric pH is very important in healing acid-related diseases and eradicating Helicobacter pylori. The duration time of intragastric pH over 3 is crucial for healing duodenal ulcers. Therefore, duration time of intragastric pH over 3 or 4 and mean or median intragastric pH become powerful tools in evaluating the drug's efficacy.

Mean intragastric pH was shown to have some linearity with AUC, 44 however, the degree of acid suppression shown by intragastric pH profile would be the best in vivo parameter with which to compare the potency of PPIs.

Pharmacokinetic properties are summarized in Table. Pharmacokinetic Property of Proton Pump Inhibitors 49 , 62 - After the clinical efficacy of omeprazole 20 mg was well studied, other PPIs were compared to omeprazole. For example, lansoprazole 30 mg was compared to omeprazole 20 mg. One study showed slightly improved acid suppression by lansoprazole 30 mg 45 while another study showed no significant difference.

Generally speaking, omeprazole, lansoprazole, pantoprazole and rabeprazole have similar efficacy for healing the acid-related diseases. S-omeprazole has an advantage on metabolism as its plasma concentration is higher than that of omeprazole. AUC of S-omeprazole was much higher than that of omeprazole. Thus, S-omeprazole, named as esomeprazole, gave improved intragastric pH profile as expected.

Since esomeprazole was superior to other PPIs for acid suppression, better healing rates on acid-related diseases were achieved. Clinical studies demonstrated that esomeprazole 40 mg od for up to 8 weeks provided higher rates of healing of erosive GERD, along with a greater proportion of patients with sustained resolution of heartburn, than omeprazole 20 mg, lansoprazole 30 mg, or pantoprazole 40 mg od.

The metabolic advantage of esomeprazole increases the plasma concentration, resulting in higher AUC, however its short half-life minutes is still the key issue in drug efficacy. There is no drug present at night. In order to keep reasonable plasma level of the drug, twice-daily dosing was designed and provided significantly greater acid suppression than once-daily dosing.

Esomeprazole 40 mg bd has also been shown to be superior to pantoprazole 40 mg bd and lansoprazole 30 mg bd in maintaining intragastric pH at 4. Twice-daily dosing of esomeprazole provides significantly greater acid suppression than once-daily dosing and may, therefore, be a reasonable consideration for patients requiring greater acid-suppression for GERD.

Recently a novel formulation of the R-enantiomer of lansoprazole has been introduced. This is a dual release formulation of 60 mg of PPI with normal enteric coating release at around pH 5. Dexlansoprazole delayed-release DR 60 mg gave better control of intragastric pH than esomeprazole 40 mg Fig.

Mean gastric pH values for dexlansoprazole DR and esomeprazole were 4. Night time pH control was significantly improved with dexlansoprazole. Comparison of dexlansoprazole modified-release MR and esomeprazole delayed-release DR.

A Mean plasma concentration-time curves of dexlansoprazole and esomeprazole after single oral doses of dexlansoprazole MR 60 mg and esomeprazole 40 mg DR capsule in healthy subjects. B Mean intragastric pH from 0 to 24 hours postdose after single oral doses of dexlansoprazole MR 60 mg open square and esomeprazole 40 mg DR capsule closed circle.

Adapted from Kukulka et al. Rabeprazole extended-release ER 50 mg formulation was developed to provide prolonged gastric acid suppression and potentially improved clinical outcomes in GERD patients. One study shows that Rabeprazole ER groups provided mean durations of There have been some concerns about the safety of PPIs. However, a randomized controlled trial that compared clopidogrel alone with the combination of clopidogrel and omeprazole found no increase in adverse cardiovascular outcomes and a reduction in the rate of adverse gastrointestinal outcomes attributable to omeprazole.

Since PPIs were introduced, considerable progress has been achieved in the management of acid-related diseases. Metabolism of PPI was different among individuals. This difference was from the variation of CYP2C19 phenotype. Better control of the intragastric pH was achieved by this specific enantiomer.

Though the shape of the plasma concentration curve or the peak level was of minor importance, AUC was relatively linear-fit with the antisecretory inhibition. Good linearity was observed between the amounts of PPI binding and the inhibition.

Measuring the intragastric pH and AUC is enough to judge the drug efficacy. DR or ER of the drug enabled the night time pH control due to prolonged time of effective plasma concentration. In patients with GERD, standard doses of esomeprazole and dexlansoprazole maintain intragastric pH above 4 for significantly longer periods compared with standard doses of other PPIs after 5 days of treatment.

Authors appreciate Dr. George Sachs and Dr. Keith Munson for informative suggestions for the function and the structure of the pump enzyme. Radioactive omeprazole bound to the enzyme was counted, and the quantity of the enzyme was determined.

Maximum binding of omeprazole to the pump enzyme with full inhibition of acid pumping was 2. The relationship was linear. Plasma level of the drug was not correlated with the inhibition or binding amounts except administration beginning time. Drug concentration in the blood abolished fast with the elimination half-life about minutes in rats, while the inhibition prolonged since the inhibition was achieved by covalent binding of activated omeprazole.

This clearly shows that measuring the plasma level of the drug cannot reveal the inhibition of the drug. Several factors must be considered to understand the pharmacodynamics of PPIs: accumulation of PPI in the parietal cell, proportion of the pump enzyme located at the canaliculus, de novo synthesis of new pump enzyme, metabolism of PPI, amounts of covalent binding of PPI in the parietal cell and the stability of PPI binding.

If covalent binding of PPI to the enzyme is inert, only de novo biosynthesis was responsible for restoration of ATPase activity. The half-life of PPI binding will be same as the half-life of the pump enzyme. Half-life of the rat pump enzyme was about 54 hours 33 but restoration of the enzyme activity after PPI administration was about 15 hours of half-life. Activated PPI binding to the pump enzyme is achieved through the disulfide forming between the activated PPI and cysteines of the enzyme.

Disulfide bond is pretty weak on reductive cleavage. In the parietal cell, there are mM of glutathione, which can cleave the disulfide. If glutathione can access the disulfide of PPI bound enzyme, glutathione can cleave the PPI, resulting in restoration of the enzyme activity. Since omeprazole binds at Cys and Cys, different accessibility of glutathione to each cysteine may result in faster cleavage. Only Cys bound omeprazole is responsible for the inhibition, in other words, restoration of the enzyme activity depends on the cleavage of disulfide of PPI at Cys Different restoration of the pump enzyme activity was observed among PPIs.

Restoration of the pump activity was much slower in pantoprazole treated rats with biphasic mode. Incubation of the inhibited ATPase with glutathione resulted in a different rate of loss in the binding of omeprazole and pantoprazole. These observations showed that removal of the drug's binding to Cys accounts for the fast phase of recovery of acid secretion, while the slow recovery occurs because of the delay in removal of the drug from Cys Thus the stability of PPI binding is one of the factors affecting the duration of the inhibitory activity.

The PPIs are inactive in their native form and are rapidly metabolized by the liver. Since PPI is an acid-activated prodrug, it is important to keep the PPI plasma level high until the gastric acid secretes. Maintaining high plasma level of the drug is significantly affected by the character of the metabolism.

Metabolism of PPIs is dependent on the cytochrome P system. Omeprazole is a racemic mixture of 2 enantiomers, R-omeprazole and S-omeprazole. Each enantiomer showed different affinity to the CYP enzyme.

Major metabolites of lansoprazole are 5-hydroxy lansoprazole and the sulfone. Similar patterns of metabolism were observed in pantoprazole and rabeprazole. It is clear that the quantity of PPI bound to the enzyme is directly linked to the inhibition of gastric acid secretion.

However, it is very difficult to measure the quantity of PPI binding in vivo, so we need another parameter substituting the quantity of PPI binding. As discussed above, the plasma level of the drug was not linear to the inhibitory activity.

It was, however, observed that the gastric antisecretory effect was related to the total dose and AUC, whereas the peak level or the shape of the curve was of minor importance. However, this relationship is only acceptable up to a certain level such as the ED50 level of dosage. Linear relationship between the inhibitory activity and AUC was not shown at higher dosage of the drug. Though the relationship between AUC and the inhibition was not linear at higher dosage of the drug due to the short half-life of the drug and the limited exposure of the enzyme to the drug, at least AUC showed the efficacy of the drug with good reliability.

Unlike the animal model, the measurement of inhibition of acid output in human is not easy, so measuring intragastric pH is used to present the inhibition due to drug activity.

Actually, control of the intragastric pH is very important in healing acid-related diseases and eradicating Helicobacter pylori. The duration time of intragastric pH over 3 is crucial for healing duodenal ulcers. Therefore, duration time of intragastric pH over 3 or 4 and mean or median intragastric pH become powerful tools in evaluating the drug's efficacy.

Mean intragastric pH was shown to have some linearity with AUC, 44 however, the degree of acid suppression shown by intragastric pH profile would be the best in vivo parameter with which to compare the potency of PPIs. Pharmacokinetic properties are summarized in Table. After the clinical efficacy of omeprazole 20 mg was well studied, other PPIs were compared to omeprazole. For example, lansoprazole 30 mg was compared to omeprazole 20 mg.

One study showed slightly improved acid suppression by lansoprazole 30 mg 45 while another study showed no significant difference. Generally speaking, omeprazole, lansoprazole, pantoprazole and rabeprazole have similar efficacy for healing the acid-related diseases. S-omeprazole has an advantage on metabolism as its plasma concentration is higher than that of omeprazole. AUC of S-omeprazole was much higher than that of omeprazole. Thus, S-omeprazole, named as esomeprazole, gave improved intragastric pH profile as expected.

Since esomeprazole was superior to other PPIs for acid suppression, better healing rates on acid-related diseases were achieved. Clinical studies demonstrated that esomeprazole 40 mg od for up to 8 weeks provided higher rates of healing of erosive GERD, along with a greater proportion of patients with sustained resolution of heartburn, than omeprazole 20 mg, lansoprazole 30 mg, or pantoprazole 40 mg od.

The metabolic advantage of esomeprazole increases the plasma concentration, resulting in higher AUC, however its short half-life minutes is still the key issue in drug efficacy.

There is no drug present at night. In order to keep reasonable plasma level of the drug, twice-daily dosing was designed and provided significantly greater acid suppression than once-daily dosing. Esomeprazole 40 mg bd has also been shown to be superior to pantoprazole 40 mg bd and lansoprazole 30 mg bd in maintaining intragastric pH at 4.

Twice-daily dosing of esomeprazole provides significantly greater acid suppression than once-daily dosing and may, therefore, be a reasonable consideration for patients requiring greater acid-suppression for GERD. In contrast to the long duration of antisecretory action, omeprazole is rapidly eliminated from plasma. The half-life is less than 1 hour, and omeprazole is almost entirely cleared from plasma within hours.

Omeprazole is completely metabolized in the liver. Interactions between H. Br Med Bull. Helicobacter pylori , proton pump inhibitors and gastroesophageal reflux disease.

Yale J Biol Med. Richard W. Sloan, M. Hospital and clinical associate professor in family and community medicine at the Milton S. This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference.

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