Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pantoprazole sodium is a substituted benzimidazole derivative which controls acid secretion by inhibition of gastric H(+)/K(+)-ATPase. The prodrug pantoprazole accumulates in the acidic space of the parietal cell where it is converted to the pharmacologically active principle, a thiophilic cyclic sulfenamide. The pH-dependent activation profile, i.e., activation at pH 1 versus activation at pH 4-6, is more favorable for pantoprazole than for the other proton pump inhibitors (PPIs) currently available. In vitro, pantoprazole interferes less potently than omeprazole with biological targets not related to gastric acid secretion. The gastric target sites for the pantoprazole sulfenamide are the cysteines 813 and 822 of the catalytic subunit of the H(+)/K(+)-ATPase. In contrast to omeprazole, the two binding sites are located right at the proton channel. In rats, dogs and humans, pantoprazole produces marked and prolonged inhibition of both basal and stimulated acid secretion. Overall, its antisecretory potency is equal to that of omeprazole. Antiulcer activity has been demonstrated for pantoprazole in two rat models. As seen with H(2)-receptor antagonists and other PPIs, pantoprazole causes an increase in serum gastrin concentration which reflects the degree of gastric acid inhibition. Pantoprazole is mainly metabolized by CYP3A4 and 2C19, but displays a lower affinity for these phase I cytochrome P450 enzymes than omeprazole. In contrast to the latter, pantoprazole is further conjugated with sulfate by the hepatic phase II metabolism. These two differences may explain why pantoprazole does not interfere with the metabolism of any other drug thus far tested in humans.
 ...
PMID:Basic aspects of selectivity of pantoprazole and its pharmacological actions. 1297 70

Proton pump inhibitors (e.g. omeprazole/esomeprazole, lansoprazole, pantoprazole, rabeprazole) have a prominent role in the short- and long-term management of acid-related intestinal disease. They are eliminated by the hepatic route and the polymorphic CYP2C19 is involved in their metabolism. Three phenotypes have been identified in various populations: extensive metabolizers (homEM), poor metabolizers (PM) and individuals carrying one wild type and one mutant allele (hetEM). Therefore, systemic drug exposure (AUC) varies widely between these three populations and the AUC for omeprazole, lansoprazole and rabeprazole are approximately 7.5-, 4.5- and 4-fold higher in PM than in homEM. Since the pharmacodynamic response to proton pump inhibitors (PPIs) is related to their AUC, intragastric pH is much more elevated in PM (median around 6) and hetEM (4 - 5) than in homEM (3 - 4). This genotype-dependent increase in AUC and intragastric pH has clinical consequences because the healing rate in peptic ulcer (PU, target pH > or = 3) and gastroesophageal reflux disease (GERD, target pH > or = 4) and the eradication of Helicobacter pylori (Hp) depend on a long-lasting (> or = 16 hours) and effective inhibition of acid secretion. Several clinical studies have shown that PM and hetEM benefit from an approximately 18% higher Hp eradication rate compared to homEM when standard dosages of PPIs are administered orally. In our own study with lansoprazole (+ amoxicillin, clarithromycin, metronidazole) the eradication rates were 100, 98 and 80% in PM, hetEM and homEM, respectively, and in patients with GERD treated with lansoprazole (30 mg/day) the healing rates after 8 weeks were much higher in PM (85 - 100%) and hetEM (68 - 95%) than in homEM (46 - 77%). In a further study with esomeprazole (40 mg/day) in 205 patients with GERD we were surprised to observe that the healing rate after 4 weeks was not dependent on the CYP2C19 genotype. In an accompanying pharmacokinetic trial in 10 patients with GERD, both esomeprazole and 5-OH-esomeprazole (formed by CYP2C19) plasma levels and those of omeprazole-sulfone (formed by CYP3A4) were determined. Based on the calculated metabolic ratios it could be shown that CYP3A4 plays a major role in kinetics of esomeprozale, particularly after multiple dosing when there is a metabolic shift in favor of the formation of the sulfone. In conclusion, for most PPIs the activity of CYP2C 19 determines the level of drug exposure (AUC), pharmacodynamic response (elevation of intragastric pH and serum levels of gastrin) and clinical outcome (Hp eradication, healing rates of PU and GERD). Thus, a genotype-adjusted dosage regimen will improve therapeutic efficacy of PPIs.
 ...
PMID:Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem. 1741 15