The Clinical Importance of Proton Pump Inhibitor Pharmacokinetics

Yacyshyn, Bruce; Thomson, A. B. R.

doi:10.1159/000065588

Cited by 45 publications

(34 citation statements)

References 41 publications

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“…Collectively, the data support better outcomes in management of GERD and higher success rate of H. pylori eradication in IM and PM phenotypes compared to NM, RM, and UM phenotypes (Table 4) [59,60,62–64], which is consistent with the higher intragastric pH achieved in patients with reduced CYP2C19 activity and higher PPI concentrations [77–79]. While many studies suggest this to be true regardless of the PPI used, some reports have suggested that the therapeutic outcomes are less influenced by genotype in PPIs with less dependence on CYP2C19 metabolism, namely rabeprazole and esomeprazole [71,73,80].…”

Section: Cyp2c19 and Ppi Pharmacogeneticssupporting

confidence: 59%

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

Rouby

Lima

Johnson

2018

Expert Opinion on Drug Metabolism & Toxicology

181

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: Cyp2c19 and Ppi Pharmacogeneticssupporting

confidence: 59%

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

Rouby

Lima

Johnson

2018

Expert Opinion on Drug Metabolism & Toxicology

181

172

View full text Add to dashboard Cite

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“…Finally, we performed multiple dose-response studies using multiple PPIs to show that the various biological responses are present at a range of doses. Importantly, the doses we used are in the micromolar range; these doses were chosen because the PPIs are found in the circulation at these concentrations, [35][36][37] thus we anticipate that this will be the range that is clinically effective. It may be worthwhile undertaking further in vitro studies using drug doses within the nanomolar range as these might shed further clues as to the mechanisms by which PPIs are exerting the diverse biological effects we have observed.…”

Section: Discussionmentioning

confidence: 99%

Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction

et al. 2017

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Preeclampsia is a severe complication of pregnancy. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. Oxidative stress and vascular inflammation exacerbate the endothelial injury. A drug that can block these pathophysiological steps would be an attractive treatment option. Proton pump inhibitors (PPIs) are safe in pregnancy where they are prescribed for gastric reflux. We performed functional studies on primary human tissues and animal models to examine the effects of PPIs on sFlt-1 and soluble endoglin secretion, vessel dilatation, blood pressure, and endothelial dysfunction. PPIs decreased sFlt-1 and soluble endoglin secretion from trophoblast, placental explants from preeclamptic pregnancies, and endothelial cells. They also mitigated tumor necrosis factor-α–induced endothelial dysfunction: PPIs blocked endothelial vascular cell adhesion molecule-1 expression, leukocyte adhesion to endothelium, and disruption of endothelial tube formation. PPIs decreased endothelin-1 secretion and enhanced endothelial cell migration. Interestingly, the PPI esomeprazole vasodilated maternal blood vessels from normal pregnancies and cases of preterm preeclampsia, but its vasodilatory effects were lost when the vessels were denuded of their endothelium. Esomeprazole decreased blood pressure in a transgenic mouse model where human sFlt-1 was overexpressed in placenta. PPIs upregulated endogenous antioxidant defenses and decreased cytokine secretion from placental tissue and endothelial cells. We have found that PPIs decrease sFlt-1 and soluble endoglin secretion and endothelial dysfunction, dilate blood vessels, decrease blood pressure, and have antioxidant and anti-inflammatory properties. They have therapeutic potential for preeclampsia and other diseases where endothelial dysfunction is involved.

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“…30) Products on the market for the treatment of gastric ulcers, including antacids, proton pump inhibitors, anticholinergic, and histamine H 2 -antagonists, can produce several adverse reactions. 31) Brazil has abundant biodiversity still underexplored. Based on a previous survey, in this work we investigated the effect of extracts of A. glandulosa on gastric lesions induced by several agents.…”

Section: Resultsmentioning

confidence: 99%