Source: Health Products Regulatory Authority (ZA) Publisher: Dezzo Trading 392 (Pty) Ltd, Jespan Centre, Corner Garrick and Flagtail Street, Extension 8, Lenasia, 1821, South Africa
Pharmacological classification: A 11.4.3 Medicines acting on the gastrointestinal tract – Other
Pharmacotherapeutic group: Drugs for acid-related disorders, proton pump inhibitors
ATC code: A02BC01
Omeprazole is a proton pump inhibitor and reduces gastric acid secretion. It is a specific inhibitor of gastric proton pump in the parietal cell.
Omeprazole is a weak base and is concentrated and converted to the active form in the acid environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme H+K+-ATPase, the proton pump. This effect on the final step of the gastric acid formation process is dose-dependent and provides for effective inhibition of both basal acid secretion and stimulated acid secretion, irrespective of the secretagogue. Omeprazole has no effect on acetylcholine, histamine or gastrin receptors.
Oral dosing with omeprazole 20 mg once daily provides inhibition of gastric acid and secretion with maximum effect being achieved within 4 days of treatment. In duodenal ulcer patients, a mean decrease of approximately 80% in twenty-four hour intragastric acidity is then maintained, with the mean decrease in peak acid output after pentagastrin stimulation being about 70%, twenty-four hours after dosing with omeprazole.
Omeprazole and omeprazole magnesium are acid labile and are therefore administered orally as enteric-coated granules in capsules. Absorption of omeprazole takes place in the small intestine and is usually completed within 3-6 hours. The systemic bioavailability of omeprazole from a single oral dose of omeprazole is approximately 35%. After repeated once daily administration, the bioavailability increases to about 60%.
Orally administered omeprazole is well absorbed but to a variable extent. Absorption of omeprazole takes place in the small intestine and is usually completed within three to six hours. Concomitant intake of food has no influence on the bioavailability.
The apparent volume of distribution in healthy subjects is approximately 0,3 L/kg and a similar value is also seen in patients with renal insufficiency. In elderly and in patients with hepatic insufficiency, the volume of distribution is slightly decreased. The plasma protein binding of omeprazole is about 95%.
Omeprazole is entirely metabolised by the cytochrome P450 (CYP), mainly in the liver. A major part of its metabolism is dependent on the polymorphically expressed, specific isoform CYP2C19 (S-mephenytoin hydroxylase) to form hydroxy-omeprazole, and to a small extent by CYP3A4 to form omeprazole sulfone. Identified metabolites in plasma are the sulfone, the sulfide and hydroxy-omeprazole, these metabolites are inactive having no significant effect on acid secretion.
About 80% of the metabolites are excreted in the urine and the rest in the faeces. The two main urinary metabolites are hydroxyl-omeprazole and the corresponding carboxylic acid.
Clearance from the plasma is with an elimination half-life of 30 to 90 minutes.
The average half-life of the terminal phase of the plasma concentration-time curve is approximately 40 minutes. There is no change in plasma half-life during treatment. The inhibition of acid secretion is related to the area under the plasma concentration-time curve (AUC) and not to the actual plasma concentration at a given time.
The absorption of omeprazole appears to be dose-dependent-increasing the dosage above 40 mg has been reported to increase the plasma concentrations in a non-linear fashion resulting in a non-linear dose-AUC relationship after repeated administration. In addition, bioavailability is higher after long-term use.
This time- and dose-dependency is due to a decrease of first pass hepatic metabolism due to saturation and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g. the sulfone).
The metabolism of omeprazole in patients with liver dysfunction is impaired, resulting in an increased area under the plasma concentration-time curve (AUC). Omeprazole has not shown any tendency to accumulate with once daily dosing (see section 4.2).
The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function (see section 4.2).
The metabolism rate of omeprazole is somewhat reduced in elderly subjects (75-79 years of age) (see section 4.2).
The major enzyme involved in omeprazole metabolism is cytochrome P450 isoenzyme CYP2C19. This enzyme is polymorphically expressed, and individuals who are deficient in the enzyme are poor metabolisers of omeprazole. This occurs in about 3% of Caucasians and 15% of Chinese, Japanese, and Koreans. These individuals have markedly higher plasma concentrations of omeprazole, and they may require dosage adjustment. Some omeprazole is metabolised by CYP3A4. and some by CYP2D6 to form desmethylomeprazole.
Limited data from children (1 year and older), do not suggest significant differences in the pharmacokinetics of omeprazole within the recommended dosages between children and adults (see sections 4.2, 4.4 and 4.8).
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