Biosteron

Pharmacodynamics. Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits the secretion of hydrochloric acid in the stomach through specific blockade of proton pumps of parietal cells. Pantoprazole is converted to its active form in the acidic environment within parietal cells, where it inhibits the enzyme H⁺-K⁺-ATPase, thereby blocking the final step of hydrochloric acid production in the stomach. This inhibition is dose-dependent and affects both basal and stimulated acid secretion. Most patients experience symptom relief within 2 weeks. Administration of pantoprazole, as with other proton pump inhibitors (PPIs) and H₂-receptor inhibitors, reduces gastric acidity and consequently increases gastrin secretion proportionally to the decrease in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme distally to the cellular receptor, it can inhibit hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is identical whether the drug is administered orally or intravenously. Fasting gastrin levels increase during pantoprazole therapy. With short-term use, they generally do not exceed the upper limit of normal. During long-term treatment, gastrin levels typically double. 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 neuroendocrine tumor precursor cells (atypical hyperplasia) or neuroendocrine tumors of the stomach, which were observed in animal studies, has not been found in humans. Based on the results of animal studies, an effect of long-term (more than one year) pantoprazole treatment on thyroid gland endocrine parameters cannot be excluded. During treatment with antisecretory agents, serum gastrin levels increase in response to decreased acid secretion. Additionally, due to reduced gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may interfere with diagnostic investigations for neuroendocrine tumors. Available published data suggest that PPI therapy should be discontinued within a period of 5 days to 2 weeks before CgA measurements. This allows CgA levels to return to the normal range, which may be falsely elevated following PPI treatment. Pharmacokinetics. Absorption. Pantoprazole is rapidly absorbed, with maximum plasma concentrations achieved after a single oral dose of 40 mg. The mean maximum serum concentration of approximately 2–3 µg/mL is reached approximately 2.5 hours after administration; concentrations remain at a steady level after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. Within the dose range of 10 to 80 mg, plasma pharmacokinetics of pantoprazole are linear for 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 consequently does not affect bioavailability. Only the variability of the lag time increases with concomitant food intake. Distribution. Serum protein binding of pantoprazole is approximately 98%. The volume of distribution is approximately 0.15 L/kg. Biotransformation. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19 followed by sulfate conjugation; other metabolic pathways include oxidation via CYP3A4. Elimination. The terminal elimination half-life is approximately 1 hour, and clearance is 0.1 L/hr/kg. A few cases of delayed elimination have been noted. Due to the specific binding of pantoprazole to the proton pumps of parietal cells, the half-life does not correlate with the much longer duration of action (acid secretion inhibition). The majority of pantoprazole metabolites are excreted in the urine (approximately 80%); the remainder is excreted in the feces. The main metabolite in both serum and urine is desmethylpantoprazole conjugated with sulfate. The half-life of the main metabolite (approximately 1.5 hours) is not much longer than the half-life of pantoprazole. Special patient populations. Poor metabolizers. Approximately 3% of Europeans have a functional deficiency of CYP2C19 enzyme activity; they are referred to as poor metabolizers. In these individuals, pantoprazole metabolism is likely primarily catalyzed by CYP3A4. After a single dose of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6-fold greater in poor metabolizers than in subjects with functionally active CYP2C19 (extensive metabolizers). 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 dialyzed. Although the main metabolite has a moderately longer half-life (2–3 hours), elimination is still rapid and accumulation does not occur. Hepatic impairment. Although the half-life increases to 7–9 hours and the AUC increases 5- to 7-fold in patients with hepatic cirrhosis (Child-Pugh classes A and B), the maximum serum concentration increases only marginally — by a factor of 1.5 compared to healthy volunteers. Elderly patients. A slight increase in AUC and Cmax in elderly volunteers compared to younger volunteers is also not clinically significant.