Controloc Mechanism of Action





Full Prescribing Info
Pharmacotherapeutic Group: Proton pump inhibitors. ATC Code: A02BC02.
Pharmacology: Pharmacodynamics: Mechanism of Action: Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps in the 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, i.e. the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose dependent and affects both basal and stimulated acid secretion. In most patients, freedom from gastric acid-related symptoms is achieved within 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and consequently increases gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the cell receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is given orally or intravenously.
The fasting gastrin values increase with pantoprazole. During short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase has only been observed in isolated cases. As a result, a mild to moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-term treatment (similar to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments (see Preclinical safety data as follows) have not been observed in humans.
An influence of long-term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid based on data observed in animal studies.
Pharmacokinetics: Absorption: Both oral and I.V. administration of pantoprazole in the dose range of 10 mg to 80 mg result in linear serum pharmacokinetics.
Controloc tab:
After ingestion, pantoprazole is rapidly absorbed into the bloodstream. On average the maximum serum concentrations (Cmax) of 1 to 1.5 μg/mL (pantoprazole 20 mg tablet) or 2 to 3 μg/mL (pantoprazole 40 mg tablet) are achieved at about 2 to 2.5 hours after administration. After single and repeated administration of pantoprazole, the pharmacokinetic characteristics of pantoprazole are very similar.
The absolute bioavailability from the tablet was found to be about 77%. Concomitant intake of food had no relevant influence either on the AUC or on the Cmax and, thus, bioavailability. Only the variability of the lag-time will be increased by concomitant food intake.
With pantoprazole granules, the peak serum concentration of 1.9 mg/l is reached after 2-2.5 hours in the fasting state. The AUC is about 5.5 mgh/l. Concomitant food intake reduces both AUC and the peak serum concentration and delays the time to peak concentration. This effect is reduced by taking pantoprazole Granules 30 minutes before breakfast.
Distribution: Pantoprazole's serum protein binding is about 98%, and in keeping with this, pantoprazole has a low volume of distribution (about 0.15 l/kg) and limited tissue distribution.
Metabolism: Pantoprazole is rapidly eliminated from the circulation and extensively metabolized in the liver. Metabolism occurs via oxidation by the CYP enzyme system, predominantly by CYP2C19 and CYP3A4 (Phase I metabolism, which is saturable). Pantoprazole undergoes further biotransformation by conjugation with sulphate, which involves the cytoplasmic enzyme sulphotransferase (phase II metabolism, which is not saturable), and which presents the main metabolism of pantoprazole.
Excretion and elimination: About 80% of the metabolites of pantoprazole are eliminated via the renal route, the rest via the feces. None of the metabolites are considered as biologically active. The main metabolite in both the serum and urine is desmethylpantoprazole, which is conjugated with sulphate. T1/2 of the main metabolite is about 1.5 hour (which is not much longer than that of pantoprazole, 1 hour).
Special populations: Impaired renal function: In patients with impaired renal function (including dialysis), pantoprazole showed no prolonged elimination half-life and no accumulation when compared with healthy subjects. No dose adjustment is necessary in patients with impaired renal function.
Impaired hepatic function: In comparison with healthy subjects, after oral administration of 40 mg pantoprazole sodium to patients with liver cirrhosis classified as Child-Pugh A and B, serum elimination half-lives of pantoprazole increased to between 3 and 6 hours (pantoprazole 20 mg tablet) or 7 to 9 hours (pantoprazole 40 mg tablet and powder) and AUC values increased by a factor of 3 to 5 (pantoprazole 20 mg tablet) or 5 to 7-fold (pantoprazole 40 mg tablet and powder). Maximum serum concentrations, Cmax, in these patients increased only slightly (1.3-fold after oral administration, 1.5-fold after I.V. application) relative to healthy subjects. The observed pharmacokinetic changes did not lead to relevant accumulation following once-daily dosing.
Age, Gender, Race: As with other clinically used PPIs, a small percentage of the population (about 3% Caucasians, 20% Asians) shows slower elimination of pantoprazole (T1/2 being up to 10 hours as compared with 1hour). Such persons are known as poor metabolizers as a result of a deficiency of the CYP2C19 enzyme. In these individuals the metabolism of pantoprazole is probably mainly catalyzed by CYP3A4. After a single-dose administration of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times higher in poor metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers). Mean peak plasma concentrations were increased by about 60 %. These findings have no implications for the posology of pantoprazole.
Results from several studies in children/adolescents from birth to 16 years indicate that the pharmacokinetics of pantoprazole is similar to those in adults when appropriately adjusted by patient weight, despite somewhat decreased clearance in patients less than 1 year old. Similar to adults, pediatric patients who were poor metabolizers of CYP2C19, exhibited reduced clearance that was more than 70% lower than the typical value.
Compared with younger subjects, slight increases in AUC and Cmax were noted after single and repeated oral administration of pantoprazole to healthy elderly subjects (age >65 years). However, no dose adjustment is necessary in elderly patients.
Drug Interactions: Pantoprazole is metabolized in the liver via the CYP enzyme system. An interaction of pantoprazole with other drugs or compounds, which are metabolized using the same enzyme system, cannot be ruled out. Nevertheless, in specific tests pantoprazole did not affect the clearance of several compounds metabolized by CYP enzymes. Vice-versa, all drugs that were tested regarding their potential influence on the pharmacokinetics of pantoprazole had no relevant effect.
No detectable interactions between pantoprazole and any other commonly prescribed co-medication tested so far were found.
Metabolism of pantoprazole occurs via oxidation by the CYP enzyme system, predominantly by CYP2C19 and CYP3A4. Interaction studies with drugs also metabolized by these pathways, like carbamazepine, diazepam, glibenclamide, nifedipine, phenytoin, and an oral contraceptive containing levonorgestrel and ethinyl estradiol did not reveal clinically significant interactions. Results from a range of interaction studies demonstrate that pantoprazole does not affect the metabolism of active substances metabolized by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), or CYP2E1 (such as ethanol) does not interfere with p-glycoprotein related absorption of digoxin. There were no interactions with concomitantly administered antacids. Interaction studies have also been performed administering pantoprazole concomitantly with the respective antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically relevant interactions were found.
Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Preclinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
In the two-year carcinogenicity studies in rats, neuroendocrine neoplasms were found. In addition, squamous cell papillomas were found in the forestomach of rats. The mechanism leading to the formation of gastric carcinoids by substituted benzimidazoles has been carefully investigated and it can be concluded that it is a secondary reaction to the massively elevated serum gastrin levels occurring in the rat during chronic high dose treatment. In the two-year rodent studies, an increased number of liver tumors was observed in rats and in female mice and was interpreted as being due to pantoprazole's high metabolic rate in the liver.
Animal Toxicology and/or Pharmacology: A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest dose (200 mg/kg). The occurrence of these neoplasms is associated with the pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As the therapeutic dose in man is low, no harmful effects to the thyroid glands are expected.
In animal reproduction studies, signs of slight fetotoxicity were observed at doses above 5 mg/kg. Investigations revealed no evidence of impaired fertility or teratogenic effects. Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, the concentration of pantoprazole in the fetus is increased shortly before birth.
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