Update on the Pharmacogenomics of Proton Pump Inhibitors

Hagymási, Krisztina; Müllner, Katalin; Herszényi, László; Tulassay, Zsolt

doi:10.2217/pgs.11.4

Cited by 89 publications

(88 citation statements)

References 69 publications

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“…The acid suppression effect of PPIs relies on the plasma concentration of the parent compound, and the AUC of the PPIs is correlated with the degree of acid inhibition [2,3]. It is therefore logical that variations in the metabolic activity of CYP2C19, for which genetic variability is a major contributor, would ultimately affect the therapeutic activity of PPIs.…”

Section: Ppi Mechanismsmentioning

confidence: 99%

“…It is well documented that the degree of acid suppression is closely related to variation in pharmacokinetic parameters (PK) of PPIs, specifically, the area under the serum (or plasma) concentration vs. time curve (AUC) [2,3]. The underlying mechanism of this variability is multifactorial and includes genetic and nongenetic factors that can alter the disposition of PPIs.…”

Section: Introductionmentioning

confidence: 99%

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Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

Rouby

Lima

Johnson

2018

Expert Opinion on Drug Metabolism & Toxicology

189

172

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Introduction: Proton Pump inhibitors (PPIs) are commonly used for a variety of acid related disorders. Despite the overall effectiveness and safety profile of PPIs, some patients do not respond adequately or develop treatment related adverse events. This variable response among patients is in part due to genotype variability of CYP2C19, the gene encoding the CYP450 (CYP2C19) isoenzyme responsible for PPIs metabolism.Areas covered: This article provides an overview of the pharmacokinetics and mechanism of action of the currently available PPIs, including the magnitude of CYPC19 contribution to their metabolism. Additionally, the role of CYP2C19 genetic variability in the therapeutic effectiveness or outcomes of PPI therapy is highlighted in details, to provide supporting evidence for the potential value of CYP2C19 genotype-guided approaches to PPI drug therapy.Expert opinion: There is a large body of evidence describing the impact of CYP2C19 variability on PPIs and its potential role in individualizing PPI therapy, yet, CYP2C19 pharmacogenetics has not been widely implemented into clinical practice. More data are needed but CYP2C19 genotype-guided dosing of PPIs is likely to become increasingly common and is expected to improve clinical outcomes, and minimize side effects related to PPIs.

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Section: Ppi Mechanismsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

Rouby

Lima

Johnson

2018

Expert Opinion on Drug Metabolism & Toxicology

189

172

View full text Add to dashboard Cite

show abstract

“…The pKa2 determines the activation rate of PPIs and affects the stability of acid suppression. The active form of the drug forms covalent disulphide bonds with cysteines accessible from the exoplasmic surface of the enzyme thus inhibiting it; studies by Sachs et al showed that proton pump inhibition is not irreversible (9)(10)(11)(12)(13)(14).…”

Section: Mechanism Of Action Of Ppismentioning

confidence: 99%

“…The half-time of recovery of gastric acid secretion in rats following inhibition by omeprazole is 15 hours; in humans it is 28 and 46 hours with omeprazole and pantoprazole, respectively (6,(10)(11)(12)(13)(14). The PPI binding pattern to cysteine (sixth transmembrane domain -TM6-) is what makes PP inhibition reversible or not; omeprazole and esomeprazole bind to cysteines 813 and 892, while lansoprazole and rabeprazole bind to cysteine 813, 892 and 321.…”

Section: What Does Reversibility Of Ppi Binding To Proton Pumps Depenmentioning

confidence: 99%

“…Glutathione, an antioxidant that protects cells from reactive oxygen species (free radicals and peroxides), cleaves disulphide bonds with cysteine 813, which is located more superficially in the membrane. On the other hand, cysteine 822 is located deep within the TM6 which makes it inaccessible to glutathione, thus rendering inhibition of gastric acid secretion more stable and less reversible (9)(10)(11)(12)(13)(14). Plasma t½ of tenatoprazole is more prolonged than that of omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole (8 versus 1-1.5 hours); therefore, its antisecretory effect last longer (13).…”

Section: What Does Reversibility Of Ppi Binding To Proton Pumps Depenmentioning

confidence: 99%

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Proton pump inhibitors in gastroesophageal reflux disease: a custom-tailored therapeutic regimen

Sobrino-Cossío

López-Alvarenga

Remes-Troche

et al. 2012

Rev. esp. enferm. dig.

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The Montreal Definition and Classification divides Gastroesophageal Reflux Disease (GERD) into esophageal symptomatic syndromes (and with mucosal damage) and extraesophageal syndromes (with acid established association and proposed association). In typical GERD symptoms, an 8-week treatment with PPIs is satisfactory in most cases (> 90%). Response rates to PPIs in GERD are highly variable, as they also rely on an appropriate clinical diagnosis of the disease; endoscopy differentiates the macroscopic GERD phenotype. The non-erosive variety (50-70% prevalence) has a different symptomatic response rate, as gastric acid is not the sole etiology of symptoms. The possible explanations of treatment failure include treatment adherence, PPI metabolism alterations and characteristics, and inadequate diagnosis. Refractory symptoms are related to gastric content neutralization by the chronic use of PPIs.Extraesophageal manifestations are associated with other pathophysiological mechanisms where an autonomic nervous system disturbance gives rise to symptoms. In these clinical entities, the relationship between symptoms and acid needs to be established in order to determine the use of PPIs, or consider other drugs. In other words, so as to "custom-tailor the best-fitting therapy" we need to answer the questions for whom, for what, how and for how long. Finally, PPI safety and tolerability are factors to be considered in elderly patients requiring chronic PPI use, who usually have chronic concomitant illnesses.

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The efficacies of esomeprazole‐ versus pantoprazole‐based reverse hybrid therapy for Helicobacter pylori eradication

Chen

Lin

Wang

et al. 2018

Adv in Digestive Medicine

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Reverse hybrid therapy, modified from the hybrid regimen by changing the sequence of drug administration, achieves a high eradication rate for Helicobacter pylori and is superior to standard triple therapy. Currently, the impacts of different proton pump inhibitors on the efficacy of this novel therapy remain unanswered. This study was conducted to compare the efficacies of esomeprazole‐ and pantoprazole‐based reverse hybrid therapies for H. pylori eradication. From August 2015 to May 2016, H. pylori‐infected patients receiving either a 14‐day esomeprazole‐ or a pantoprazole‐based reverse hybrid therapy (esomeprazole or pantoprazole 40 mg and amoxicillin 1 g twice‐daily for 14 days, plus clarithromycin 500 mg and metronidazole 500 mg twice‐daily for the initial seven days) for H. pylori eradication were included in the retrospective study. All the patients underwent a follow‐up endoscopy with a rapid urease test and histological examination or a urea breath test at eight weeks after the end of anti‐H. pylori therapy to assess H. pylori status. To determine the independent factors affecting the treatment response, 12 clinical and endoscopic parameters were analyzed by multivariate analysis. In all, 123 H. pylori‐infected outpatients were included for this study. Among them, 62 received the esomeprazole‐based regimen and 61 received the pantoprazole‐based regimen. Intention‐to‐treat (ITT) analysis demonstrated no differences in eradication rate between esomeprazole‐ and pantoprazole‐based groups (90% vs 97%; P = 0.273). Modified ITT (90% vs 98%) and per‐protocol analysis (92% vs 98%) yielded similar results (P = 0.115 and 0.116, respectively). Both groups had comparable frequencies of adverse events (16% vs 21%; P = 0.779) and drug compliance (98% and 93%; P = 0.207). The eradication rates were significantly related to increased body fat percentage (P = 0.002) and the presence of diabetes (P = 0.033). Multivariate analysis disclosed an increased body fat percentage (odds ratio: 0.072, 95% confidence interval: 0.008‐0.623), which was the only independent predictor of treatment failure. Esomeprazole‐ and pantoprazole‐based reverse hybrid regimens have comparable anti‐H. pylori efficacy and both achieve an eradication rate more than 90%. Increased body fat percentage is a clinical factor predicting eradication failure of reverse hybrid therapy.

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Update on the Pharmacogenomics of Proton Pump Inhibitors

Cited by 89 publications

References 69 publications

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

Proton pump inhibitors in gastroesophageal reflux disease: a custom-tailored therapeutic regimen

The efficacies of esomeprazole‐ versus pantoprazole‐based reverse hybrid therapy for Helicobacter pylori eradication

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