Biopronil spot-on

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 in parietal cells. Pantoprazole is converted to its active form in the acidic environment of parietal cells, where it inhibits the H⁺/K⁺-ATPase enzyme, thereby blocking the final step in the production of hydrochloric acid in the stomach. This inhibition is dose-dependent and affects both basal and stimulated acid secretion. Most patients achieve symptom relief within 2 weeks. Administration of pantoprazole, as with other proton pump inhibitors (PPIs) and H₂-receptor antagonists, reduces gastric acidity and thus increases gastrin secretion proportionally to the decrease in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme distally relative to the cell receptor, it can inhibit hydrochloric acid secretion independently 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, these levels do not exceed the upper limit of normal in most cases. With 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 enterochromaffin-like (ECL) cells in the stomach is observed (similar to adenomatoid hyperplasia). Nevertheless, according to studies conducted to date, the formation of neuroendocrine tumour precursor cells (atypical hyperplasia) or neuroendocrine tumours 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 endocrine parameters cannot be excluded. During treatment with antisecretory medicinal products, serum gastrin levels increase in response to the reduction in acid secretion. Additionally, 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 have been falsely elevated following PPI treatment. Pharmacokinetics. Absorption. Pantoprazole is rapidly absorbed, and maximum plasma concentrations are 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; the concentration remains stable after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. Over the dose range of 10 to 80 mg, the plasma pharmacokinetics of pantoprazole remain linear for both oral and intravenous administration. The absolute bioavailability of the tablets is approximately 77%. Concomitant food intake does not affect AUC (area under the concentration–time curve) or maximum serum concentration, and therefore 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 metabolised almost exclusively in the liver. The main metabolic pathway is demethylation by CYP2C19 followed by sulphate conjugation; other metabolic pathways include oxidation by 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 the proton pumps of parietal cells, the half-life does not correlate with the considerably 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 itself. Special patient populations. Poor metabolisers. Approximately 3% of Europeans have a functional deficiency of CYP2C19 enzyme activity; they are referred to as poor metabolisers. In these individuals, the metabolism of pantoprazole is likely catalysed primarily by CYP3A4. After a single 40 mg dose of pantoprazole, the mean area under the plasma concentration–time curve was approximately 6-fold higher in poor metabolisers than in subjects 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 pantoprazole is administered to patients with impaired renal function (including patients on dialysis). As in healthy individuals, the half-life of pantoprazole in these patients is short. Only very small amounts of pantoprazole are dialysable. Despite the moderately prolonged half-life of the main metabolite (2–3 hours), elimination remains 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 AUC increases 5- to 7-fold, the maximum serum concentration increases only slightly — approximately 1.5-fold 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.