Omeprazole pharmacokinetics and molecular data

Pharmacokinetics
Absorption Metabolites Biovailability Considerations for Asian patients Administration with applesauce Combination therapy with antimicrobials Mechanism of action Antisecretory activity Enterochromaffin-like (ECL) cell effects Serum gastrin effects Other effects
 * Relaxation and prevention of coronary artery spasm
 * Bioavailabilty (chronic renal impairment)
 * Bioavailabilty (elderly)

Absorption
Omeprazole Delayed-Release Capsules contain an enteric-coated microtablet formulation of Omeprazole (because Omeprazole is acid-labile), so that absorption of Omeprazole begins only after the microtablets leave the stomach. Absorption is rapid, with peak plasma levels of Omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of Omeprazole and AUC are approximately proportional to doses up to 40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared to intravenous administration) is about 30-40% at doses of 20-40 mg, due in large part to presystemic metabolism. In healthy subjects, the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500-600 mL/min. Protein binding is approximately 95%. Return to top

Metabolites
Following single dose oral administration of a buffered solution of Omeprazole, little if any unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six metabolites. Two were identified as hydroxyOmeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of Omeprazole. Three metabolites have been identified in plasma — the sulfide and sulfone derivatives of Omeprazole, and hydroxyOmeprazole. These metabolites have very little or no antisecretory activity. Return to top

Bioavailability
The bioavailability of Omeprazole increases slightly upon repeated administration of Omeprazole Delayed-Release Capsules. Return to top

Bioavailability (chronic hepatic disease)
In patients with chronic hepatic disease, the bioavailability increased to approximately 100% compared to an I.V. dose, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared to the half-life in normals of 0.5-1 hour. Plasma clearance averaged 70 mL/min, compared to a value of 500-600 mL/min in normal subjects. Return to top

Bioavailabilty (chronic renal impairment)
In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62 mL/min/1.73 m2, the disposition of Omeprazole was very similar to that in healthy volunteers, although there was a slight increase in bioavailability. Because urinary excretion is a primary route of excretion of Omeprazole metabolites, their elimination slowed in proportion to the decreased creatinine clearance. Return to top

Bioavailabilty (elderly)
The elimination rate of Omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of Omeprazole (buffered solution) was administered to healthy elderly volunteers, versus 58% in young volunteers given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of Omeprazole and no unchanged drug was detected. The plasma clearance of Omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers. Return to top

Considerations for Asian patients
In pharmacokinetic studies of single 20 mg Omeprazole doses, an increase in AUC of approximately four-fold was noted in Asian subjects compared to Caucasians. Dose adjustment, particularly where maintenance of healing of erosive esophagitis is indicated, for the hepatically impaired and Asian subjects should be considered. Return to top

Administration with applesauce
Omeprazole Delayed-Release Capsule 40 mg was bioequivalent when administered with and without applesauce. However, Omeprazole Delayed-Release Capsule 20 mg was not bioequivalent when administered with and without applesauce. When administered with applesauce, a mean 25% reduction in Cmax was observed without a significant change in AUC for Omeprazole Delayed-Release Capsule 20 mg. The clinical relevance of this finding is unknown. Return to top

Combination therapy with antimicrobials
Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to healthy adult male subjects. The steady state plasma concentrations of Omeprazole were increased (Cmax, AUC0-24, and T1/2 increases of 30%, 89% and 34% respectively) by the concomitant administration of clarithromycin. The observed increases in Omeprazole plasma concentration were associated with the following pharmacological effects. The mean 24-hour gastric pH value was 5.2 when Omeprazole was administered alone and 5.7 when co-administered with clarithromycin. The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of Omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with Omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of Omeprazole. The pharmacokinetics of Omeprazole, clarithromycin, and amoxicillin have not been adequately studied when all three drugs are administered concomitantly. Return to top

Mechanism of action
Omeprazole belongs to a new class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonistic properties, but that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, Omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after rapid disappearance from plasma, Omeprazole can be found within the gastric mucosa for a day or more. Return to top

Antisecretory activity
After oral administration, the onset of the antisecretory effect of Omeprazole occurs within one hour, with the maximum effect occurring within two hours. Inhibition of secretion is about 50% of maximum at 24 hours and the duration of inhibition lasts up to 72 hours. The antisecretory effect thus lasts far longer than would be expected from the very short (less than one hour) plasma half-life, apparently due to prolonged binding to the parietal H+/K+ ATPase enzyme. When the drug is discontinued, secretory activity returns gradually, over 3 to 5 days. The inhibitory effect of Omeprazole on acid secretion increases with repeated once-daily dosing, reaching a plateau after four days. Single daily oral doses of Omeprazole ranging from a dose of 10 mg to 40 mg have produced 100% inhibition of 24-hour intragastric acidity in some patients. Return to top

Enterochromaffin-like (ECL) cell effects
In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists. Human gastric biopsy specimens have been obtained from more than 3000 patients treated with Omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients. However, these studies are of insufficient duration and size to rule out the possible influence of long-term administration of Omeprazole on the development of any premalignant or malignant conditions. Return to top

Serum gastrin effects
In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of Omeprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment. In comparison with histamine H2-receptor antagonists, the median increases produced by 20 mg doses of Omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase). Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy. Return to top

Other effects
Systemic effects of Omeprazole in the CNS, cardiovascular and respiratory systems have not been found to date. Omeprazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin. No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after a single dose of Omeprazole 90 mg. In healthy subjects, a single I.V. dose of Omeprazole (0.35 mg/kg) had no effect on intrinsic factor secretion. No systematic dose-dependent effect has been observed on basal or stimulated pepsin output in humans. However, when intragastric pH is maintained at 4.0 or above, basal pepsin output is low, and pepsin activity is decreased. As do other agents that elevate intragastric pH, Omeprazole administered for 14 days in healthy subjects produced a significant increase in the intragastric concentrations of viable bacteria. The pattern of the bacterial species was unchanged from that commonly found in saliva. All changes resolved within three days of stopping treatment. The course of Barrett’s esophagus in 106 patients was evaluated in a U.S. double-blind controlled study of Omeprazole 40 mg b.i.d. for 12 months followed by 20 mg b.i.d. for 12 months or ranitidine 300 mg b.i.d. for 24 months. No clinically significant impact on Barrett’s mucosa by antisecretory therapy was observed. Although neosquamous epithelium developed during anti-secretory therapy, complete elimination of Barrett’s mucosa was not achieved. No significant difference was observed between treatment groups in development of dysplasia in Barrett’s mucosa and no patient developed esophageal carcinoma during treatment. No significant differences between treatment groups were observed in development of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal metaplasia, or colon polyps exceeding 3 mm in diameter. Return to top