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Pharmacodynamics. Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits the secretion of hydrochloric acid in the stomach through specific blockade of the proton pumps of parietal cells. Pantoprazole is converted to its active form in the acidic environment of the parietal cells, where it inhibits the H⁺/K⁺-ATPase enzyme, thereby blocking the final step of hydrochloric acid production in the stomach. The inhibition is dose-dependent and affects both basal and stimulated acid secretion. Most patients become symptom-free within 2 weeks. Treatment with pantoprazole, as with other proton pump inhibitors (PPIs) and H2-receptor antagonists, reduces gastric acidity and thereby increases gastrin secretion proportionally to the decrease in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds to the enzyme distal to the cellular receptor, it can inhibit hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the drug is administered orally or intravenously. During pantoprazole therapy, fasting gastrin levels increase. With short-term use, they do not exceed the upper limit of normal in most cases. During long-term treatment, gastrin levels double in most cases. Excessive increases occur only in isolated cases. As a result, in a small number of cases during long-term treatment, a mild to moderate increase in specific endocrine (ECL) cells in the stomach is observed (similar to adenomatoid hyperplasia). However, according to studies conducted to date, the formation of carcinoid precursor cells (atypical hyperplasia) or gastric neuroendocrine tumours, which were found in animal studies, has not been observed in humans. Based on the results of animal studies, the influence of long-term (more than one year) pantoprazole treatment on endocrine parameters of the thyroid gland cannot be excluded. During treatment with antisecretory medicinal products, serum gastrin levels rise in response to decreased acid secretion. In addition, due to decreased gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may interfere with diagnostic investigations for neuroendocrine tumours. Available published data suggest that PPI therapy should be discontinued within a period of 5 days to 2 weeks prior to CgA measurements. This allows CgA levels to return to the normal range, which may be falsely elevated after PPI treatment. Pharmacokinetics. Absorption. Pantoprazole is rapidly absorbed, and maximum plasma concentrations are achieved after a single oral dose of 40 mg. The maximum serum concentration of approximately 2–3 µg/ml is reached on average 2.5 hours after administration; the concentration remains constant after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10 to 80 mg, the pharmacokinetics of pantoprazole in plasma remain linear with both oral and intravenous administration. The absolute bioavailability of the tablets is approximately 77%. Concomitant food intake does not affect the AUC (area under the concentration–time curve) or the maximum serum concentration, and accordingly does not affect bioavailability. Only the variability of the lag time increases with concomitant food intake. Distribution. Pantoprazole serum protein binding is approximately 98%. The volume of distribution is approximately 0.15 L/kg. Biotransformation. The substance is metabolised almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19 followed by sulphate conjugation; other metabolic pathways include oxidation via CYP3A4. Elimination. The terminal half-life is approximately 1 hour and the clearance is 0.1 L/h/kg. A few cases of delayed elimination have been noted. Due to the specific binding of pantoprazole to parietal cell proton pumps, the half-life does not correlate with the much longer duration of action (inhibition of acid secretion). The majority of pantoprazole metabolites are excreted renally (approximately 80%); the remainder is excreted in faeces. The main metabolite in both serum and urine is desmethylpantoprazole conjugated with sulphate. The half-life of the main metabolite (approximately 1.5 hours) is not much longer than that of pantoprazole. Special patient populations. Poor metabolisers. Approximately 3% of Europeans lack functional CYP2C19 enzyme activity; they are referred to as poor metabolisers. In these individuals, pantoprazole metabolism is probably catalysed mainly by CYP3A4. After administration of a single 40 mg dose of pantoprazole, the mean area under the plasma concentration–time curve was approximately 6 times greater in poor metabolisers than in individuals with functionally active CYP2C19 (extensive metabolisers). The mean peak plasma concentration increased by approximately 60%. These findings do not affect the dosing of pantoprazole. Renal impairment. No dose reduction is recommended when prescribing pantoprazole to patients with impaired renal function (including patients on dialysis). As in healthy individuals, the half-life of pantoprazole is short. Only very small amounts of pantoprazole are dialysed. Although the main metabolite has a moderately prolonged half-life (2–3 hours), elimination is still rapid and therefore accumulation does not occur. Hepatic impairment. Although in patients with hepatic cirrhosis (Child-Pugh classes A and B) the half-life increases to 7–9 hours and the AUC increases 5–7-fold, the maximum serum concentration increases only slightly — by a factor of 1.5 compared with healthy volunteers. Elderly patients. A slight increase in AUC and Cmax in elderly volunteers compared with younger volunteers is also of no clinical significance.