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 enzyme H⁺/K⁺-ATPase, 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 experience symptom relief within 2 weeks. Administration of pantoprazole, as with other proton pump inhibitors (PPIs) and H₂-receptor antagonists, 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 cell 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 treatment with pantoprazole. With short-term use, they generally do not exceed the upper limit of normal. During long-term treatment, gastrin levels in most cases increase twofold. Excessive elevation occurs 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, formation of carcinoid precursor cells (atypical hyperplasia) or gastric neuroendocrine tumours, which were observed in animal studies, has not been found in humans. Based on the results of animal studies, the 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 reduced acid secretion. In addition, due to decreased gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may interfere with the results of investigations for neuroendocrine tumours. Available published data suggest that PPI treatment 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 following PPI treatment. Pharmacokinetics. Absorption. Pantoprazole is rapidly absorbed, and peak plasma concentrations are achieved after a single oral dose of 40 mg. Peak serum concentrations of approximately 2–3 µg/mL are reached on average 2.5 hours after administration; concentrations remain at a steady level after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10 to 80 mg, the plasma pharmacokinetics of pantoprazole are linear after 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 peak serum concentration, and consequently 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 by CYP2C19 followed by sulphate conjugation; other metabolic pathways include oxidation by CYP3A4. Elimination. The terminal elimination 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 proton pumps in parietal cells, the elimination half-life does not correlate with the much longer duration of action (acid secretion inhibition). 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. Slow metabolisers. Approximately 3% of Europeans lack functional CYP2C19 enzyme activity and are referred to as poor metabolisers. In these individuals, pantoprazole metabolism is likely mainly catalysed by CYP3A4. After a single dose of 40 mg pantoprazole, the mean area under the plasma concentration–time curve was approximately 6 times greater in poor metabolisers than in subjects with functionally active CYP2C19 (extensive metabolisers). The mean peak plasma concentration was increased by approximately 60%. These findings do not affect the dosing recommendations for pantoprazole. Renal impairment. No dose reduction is recommended when prescribing pantoprazole to patients with impaired renal function (including patients on dialysis). As in healthy subjects, 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 no accumulation occurs. Hepatic impairment. Although in patients with hepatic cirrhosis (Child-Pugh class A and B) the half-life increases to 7–9 hours and the AUC increases 5- to 7-fold, the peak serum concentration increases only slightly — by a factor of 1.5 compared with that in healthy volunteers. Elderly patients. The slight increase in AUC and Cmax in elderly volunteers compared with younger volunteers is also not clinically significant.