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      Pharmacokinetics and Pharmacodynamics of the Proton Pump Inhibitors

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          Abstract

          Proton pump inhibitor (PPI) is a prodrug which is activated by acid. Activated PPI binds covalently to the gastric H +, K +-ATPase via disulfide bond. Cys813 is the primary site responsible for the inhibition of acid pump enzyme, where PPIs bind. Omeprazole was the first PPI introduced in market, followed by pantoprazole, lansoprazole and rabeprazole. Though these PPIs share the core structures benzimidazole and pyridine, their pharmacokinetics and pharmacodynamics are a little different. Several factors must be considered in understanding the pharmacodynamics of PPIs, including: accumulation of PPI in the parietal cell, the proportion of the pump enzyme located at the canaliculus, de novo synthesis of new pump enzyme, metabolism of PPI, amounts of covalent binding of PPI in the parietal cell, and the stability of PPI binding. PPIs have about 1hour of elimination half-life. Area under the plasmic concentration curve and the intragastric pH profile are very good indicators for evaluating PPI efficacy. Though CYP2C19 and CYP3A4 polymorphism are major components of PPI metabolism, the pharmacokinetics and pharmacodynamics of racemic mixture of PPIs depend on the CYP2C19 genotype status. S-omeprazole is relatively insensitive to CYP2C19, so better control of the intragastric pH is achieved. Similarly, R-lansoprazole was developed in order to increase the drug activity. Delayed-release formulation resulted in a longer duration of effective concentration of R-lansoprazole in blood, in addition to metabolic advantage. Thus, dexlansoprazole showed best control of the intragastric pH among the present PPIs. Overall, PPIs made significant progress in the management of acid-related diseases and improved health-related quality of life.

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          Proton pump inhibitors: an update of their clinical use and pharmacokinetics.

          Proton pump inhibitors (PPIs) represent drugs of first choice for treating peptic ulcer, Helicobacter pylori infection, gastrooesophageal reflux disease, nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal lesions (complications), and Zollinger-Ellison syndrome. The available agents (omeprazole/esomeprazole, lansoprazole, pantoprazole, and rabeprazole) differ somewhat in their pharmacokinetic properties (e.g., time-/dose-dependent bioavailability, metabolic pattern, interaction potential, genetic variability). For all PPIs, there is a clear relationship between drug exposure (area under the plasma concentration/time curve) and the pharmacodynamic response (inhibition of acid secretion). Furthermore, clinical outcome (e.g., healing and eradication rates) depends on maintaining intragastric pH values above certain threshold levels. Thus, any changes in drug disposition will subsequently be translated directly into clinical efficiency so that extensive metabolizers of CYP2C19 will demonstrate a higher rate of therapeutic nonresponse. This update of pharmacokinetic, pharmacodynamic, and clinical data will provide the necessary guide by which to select between the various PPIs that differ-based on pharmacodynamic assessments-in their relative potencies (e.g., higher doses are needed for pantoprazole and lansoprazole compared with rabeprazole). Despite their well-documented clinical efficacy and safety, there is still a certain number of patients who are refractory to treatment with PPIs (nonresponder), which will leave sufficient space for future drug development and clinical research.
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            Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study.

            Proton pump inhibitors owe their clinical efficacy to their ability to suppress gastric acid production. The objective of this study was to evaluate and compare intragastric pH following standard doses of esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole. This randomized, open-label, comparative five-way crossover study evaluated the 24-h intragastric pH profile of oral esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg, and rabeprazole 20 mg once daily in 34 Helicobacter pylori-negative patients aged 18-60 yr with symptoms of gastroesophageal reflux disease. Patients were randomly assigned to one of five treatment sequences and study drug was taken on 5 consecutive mornings 30 minutes prior to a standardized breakfast. A washout period of at least 10 days separated each treatment phase. Thirty-four patients provided evaluable data for all five comparators. The mean number of hours of evaluable pH data was > or =23.75 hours. On day 5, intragastric pH was maintained above 4.0 for a mean of 14.0 h with esomeprazole, 12.1 h with rabeprazole, 11.8 h with omeprazole, 11.5 h with lansoprazole, and 10.1 h with pantoprazole (p < or = 0.001 for differences between esomeprazole and all other comparators). Esomeprazole also provided a significantly higher percentage of patients with an intragastric pH greater than 4.0 for more than 12 h relative to the other proton pump inhibitors (p < 0.05). The frequency of adverse events was similar between treatment groups. Esomeprazole at the standard dose of 40 mg once daily provided more effective control of gastric acid at steady state than standard doses of lansoprazole, omeprazole, pantoprazole, and rabeprazole in patients with symptoms of gastroesophageal reflux disease.
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              Influence of CYP2C19 pharmacogenetic polymorphism on proton pump inhibitor-based therapies.

              Proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, rabeprazole, esomeprazole, and pantoprazole, are mainly metabolized by CYP2C19 in the liver. There are genetically determined differences in the activity of this enzyme. The genotypes of CYP2C19 are classified into the three groups, rapid extensive metabolizer (RM), intermediate metabolizer (IM), and poor metabolizer (PM). The pharmacokinetics and pharmacodynamics of PPIs depend on CYP2C19 genotype status. Plasma PPI levels and intragastric pHs during PPI treatment in the RM group are lowest, those in the IM group come next, and those in the PM group are highest of the three groups. These CYP2C19 genotype-dependent differences in pharmacokinetics and pharmacodynamics of PPIs influence the cure rates for the gastro-esophageal reflux disease and H. pylori infection by PPI-based therapies. For the better PPI-based treatment, doses and dosing schemes of PPIs should be optimized based on CYP2C19 genotype status.
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                Author and article information

                Journal
                J Neurogastroenterol Motil
                J Neurogastroenterol Motil
                JNM
                Journal of Neurogastroenterology and Motility
                Korean Society of Neurogastroenterology and Motility
                2093-0879
                2093-0887
                January 2013
                08 January 2013
                : 19
                : 1
                : 25-35
                Affiliations
                [1 ]Jai Scientific, Los Angeles, California, USA.
                [2 ]Division of Gastroenterology, Seoul National University Bundang Hospital, and Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
                Author notes
                Correspondence: Jai Moo Shin, PhD. 20000 Tuba Street, Chatsworth, CA 91311, USA. Tel: +1-818-523-6913, jaimooshin@ 123456gmail.com
                Article
                10.5056/jnm.2013.19.1.25
                3548122
                23350044
                628aa28e-e59f-48f4-8830-768ba23f6a00
                © 2013 The Korean Society of Neurogastroenterology and Motility

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 December 2012
                : 20 December 2012
                : 21 December 2012
                Categories
                Review

                Neurology
                area under the plasmic concentration curve,hydrogen potassium atpase,gastric acid,gastric endogenous activator protein, mammal,pharmacokinetics,pharmacology,proton pump inhibitors

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