Interaction Of Proton Pump Inhibitors Research Articles

Mechanistic Insight into the Inhibition of Choline Acetyltransferase by Proton Pump Inhibitors.

Various pharmacoepidemiological investigational studies have indicated that Proton Pump Inhibitors (PPIs) may increase the likelihood of developing Alzheimer's disease (AD) and non-AD related dementias. Previously, we have reported the inhibition of the acetylcholine biosynthesizing enzyme choline acetyltransferase (ChAT) by PPIs, for which omeprazole, lansoprazole, and pantoprazole exhibited IC50 values of 0.1, 1.5, and 5.3 μM, respectively. In this study we utilize a battery of computational tools to perceive a mechanistic insight into the molecular interaction of PPIs with the ChAT binding pocket that may further help in designing novel ChAT ligands. Various in-silico tools make it possible for us to elucidate the binding interaction, conformational stability, and dynamics of the protein-ligand complexes within a 200 ns time frame. Further, the binding free energies for the PPI-ChAT complexes were explored. The results suggest that the PPIs exhibit equal or higher binding affinity toward the ChAT catalytic tunnel and are stable throughout the simulated time and that the pyridine ring of the PPIs interacts primarily with the catalytic residue His324. A free energy landscape analysis showed that the folding process was linear, and the residue interaction network analysis can provide insight into the roles of various amino acid residues in stabilization of the PPIs in the ChAT binding pocket. As a major factor for the onset of Alzheimer's disease is linked to cholinergic dysfunction, our previous and the present findings give clear insight into the PPI interaction with ChAT. The scaffold can be further simplified to develop novel ChAT ligands, which can also be used as ChAT tracer probes for the diagnosis of cholinergic dysfunction and to initiate timely therapeutic interventions to prevent or delay the progression of AD.

Differential effects of proton pump inhibitors and vonoprazan on vascular endothelial growth factor expression in cancer cells.

Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion, used as first-line agents in treating peptic ulcers. However, we have previously reported that PPIs may diminish the therapeutic effect of anti-vascular endothelial growth factor (VEGF) drugs in patients with cancer. In this study, we explored the effects of vonoprazan, a novel gastric acid secretion inhibitor used for the treatment of peptic ulcers, on the secretion of VEGF in cancer cells and attempted to propose it as an alternative PPI for cancer chemotherapy.The effects of PPI and vonoprazan on VEGF expression in cancer cells were compared by real-time reverse transcription-polymerase chain reactionand ELISA. The interaction of vonoprazan and PPIs with transcriptional regulators by docking simulation analysis.In various cancer cell lines, including the human colorectal cancer cell line (LS174T), PPI increased VEGF messengerRNA expression and VEGF protein secretion, while this effect was not observed with vonoprazan. Molecular docking simulation analysis showed that vonoprazan had a lower binding affinity for estrogen receptor alpha (ER-α), one of the transcriptional regulators of VEGF, compared to PPI. Although the PPI-induced increase in VEGF expression was counteracted by pharmacological ER-α inhibition, the effect of vonoprazan on VEGF expression was unchanged.Vonoprazan does not affect VEGF expression in cancer cells, which suggests that vonoprazan might be an alternative to PPIs, with no interference with the therapeutic effects of anti-VEGF cancer chemotherapy.

Proton pump inhibitors have pH-dependent effects on the thermostability of the carboxyl-terminal domain of voltage-gated proton channel Hv1.

The voltage-gated proton channel Hv1 is highly selective for H+ and is activated by membrane depolarization and pH gradient. An increased external and decreased internal pH opens the Hv1 channel. The intracellular C-terminal domain of Hv1 is responsible for channel dimerization, cooperative, and thermosensitive gating. Here, we found that proton pump inhibitors (PPIs) interact with the C-terminal domain of human Hv1. The interaction between PPIs and the C-terminal domain, which is pH-dependent, lowered the thermal and structural stability of the protein at pH 4, but enhanced the thermal and structural stability at pH 8. Furthermore, we investigated in vitro the interaction of PPIs with the C-terminal domain of Hv1 by fluorescence and micro-Raman spectra. Fluorescence quenching measurements revealed that the interaction between the C-terminal domain and PPIs is a mainly hydrophobic interaction. The micro-Raman spectra showed that PPIs did not form stable disulfide bonds with the unique thiol group within this domain (Cys249 residue). The preferential interaction of PPIs with the inactive form of Hv1 stabilizes the high pH inactive state of the C-terminal domain, indicating a mechanism by which PPIs might act explicitly on the stabilization of a closed state of the proton channel.

Prescription behavior for gastroprotective drugs in new users as a result of communications regarding clopidogrel - proton pump inhibitor interaction.

Safety concerns of the concomitant use of clopidogrel and proton pump inhibitors (PPIs) were published in 2009 and 2010 by the medicines regulatory agencies, including a direct healthcare professional communication. We examined the association between various safety statements and prescription behavior for gastroprotective drugs in naïve patients in the Netherlands during the years 2008–2011. Data from the PHARMO Database Network were analyzed with interrupted time series analyses to estimate the impact of each communication on drug prescriptions. Dispensings were used as a proxy variable for prescription behavior. After the early communication in January 2009, 15.5% (95% CI 7.8, 23.4) more patients started concomitantly with (es)omeprazole and 13.8% (95% CI 6.5, 21.2) less with other PPIs. Directly after the first statement in June 2009, we found a steep increase in histamine 2‐receptor antagonists (H2RA) peaking at 25%, placing those patients at risk for gastrointestinal events. This effect for H2RA faded away after a few months. In February 2010, when the official advice via an adjusted statement was to avoid (es)omeprazole, we found a decrease of 11.9% (95% CI 5.7, 18.2) for (es)omeprazole and an increase of +16.0% (95% CI 10.3, 21.7) for other PPIs. Still 22.6% (95% CI 19.5, 25.7) of patients started on (es)omeprazole in February 2010, placing them at risk for cardiovascular events. Advices of regulatory authorities were followed, however, reluctantly and not fully, probably partly because of the existing scientific doubt about the interaction.

Cyclic Voltammetric Study of the Interaction of Biologically Important Metal Ion with Proton Pump Inhibitors

Electrochemical studies on the interaction of Fe(III) with proton pump inhibitors (PPIs) (omeprazole, pantoprazole, esomeprazole and rabeprazole) in acetate buffer solution were carried out at gassy carbon electrode (GCE) at various pH (3.5, 4.0 and 4.5). In presence of omeprazole (Ome), the anodic and cathodic peak current for Fe(III) decreased in comparison to solely Fe(III). However, in some cases both the peaks were almost disappeared. Moreover, anodic and cathodic peaks shifted significantly towards negative potential. This is an indication that a strong interaction occurred between Fe(III) and Ome. The maximum interaction is found at 1:2 molar ratio of Fe(III) and Ome at above mentioned pH. The electrochemical interaction of Fe(III) and other PPIs was found as identical with the behavior of Ome. The electrochemical study of the interactions between metal ions and PPIs would provide important information for the technological application of PPIs in human body.Dhaka Univ. J. Sci. 64(1): 25-30, 2016 (January)

ASSA14-03-35 Effects of Omeprazole and Pantoprazole on platelet function in Acute Coronary Syndrome patients receiving clopidogrel: A Single-centre Prospective Randomised Controlled Clinical Trials

<h3>Background</h3> Proton pump inhibitors (PPIs) are usually prescribed to patients undergoing dual antiplatelet therapy to decrease the risk of gastrointestinal bleeding. However, the proportion of patients increased incidence of major adverse cardiovascular event because of interaction of PPIs and clopidogrel. The aim of the study was to assess the effect of omeprazole and pantoprazole on platelet reactivity in acute coronary syndrome patients receiving clopidogrel. <h3>Method</h3> From October 2012 to September 2013, a total of 620 consecutive acute coronary syndrome patients from Shenyang General Hospital were enrolled. All patients received clopidogrel loading dose 300 mg and aspirin 300 mg. Patients were randomised to two groups by the ratio of 1:1 and received routine dual anti-platelet treatment. The omeprazole group (aspirin 300 mg/d and clopidogrel 75 mg/d and omeprazole 20 mg/d, n = 310). The pantoprazole group (aspirin 300 mg/d and clopidogrel 75 mg/d and pantoprazole 20 mg/d, n = 310). The reversion rate of ADP which was defined as 20 μmol/L adenosine diphosphate induced platelet aggregation (by LTA) (on admission, three days and 30 days after dual antiplatelet therapy) and clinical events (stent thrombosis, MACEs, which included cardiac death, myocardial infarction or ischaemic symptoms driven target vessel revascularisation, all-cause death, TIMI) were observed. <h3>Result</h3> All groups were generally well balanced with regard to baseline demographic, clinical, and proced-ural characteristics. There were no different on platelet response to clopidogrel at three days (52.8% ± 19.3% vs 50.2% ± 19.3%, respectively, p = 0.384) and 30 days (49.9% ± 14.9% vs 49.1% ± 14.7%, respectively, p = 0.559) between omeprazole group and pantoprazole group. 1 stent thrombosis in the omeprazole group and 0 stent thrombosis in pantoprazole group (p = 0.219). 2 patients in omeprazole group were suffered from MACE (0.6%), and 3 patients in pantoprazole group (0.97%, p = 0.359). In addition, there were no major or minor bleeding in the two groups, the minimal bleeding in omeprazole and pantoprazole groups were no significantly difference (2.1% vs 2.8%, respectively, p = 0.235). There was no significantly association between the two groups for all-cause death (p = 0.687), and 1 patient died due to the traumatic brain injury in the omeprazole group. <h3>Conclusion</h3> These results suggest that the drug interaction between PPIs (omeprazole and pantoprazole)and clopidogrel does not result in ADP induced platelet aggregation. There was no apparent clinical events interaction between clopidogrel and omeprazole and pantoprazole in patients who received dual antiplatelet therapy. The clinic impact of this strategy needs to be proved by long term follow-up outcome studies.

The Pharmacogenetics of Cytochrome P450 2C19 Enzymes - Effects on Clopidogrel and Proton Pump Inhibitors

BACKGROUND: Cytochrome P450 (CYP) enzymes play important roles in human, including drug metabolism. CYP2 is the largest family of human CYP, with its sequence comprising almost one third of all CYP sequences, and responsible for the metabolism of approximately 2% of clinically administrated drugs. One of the most important enzymes in this family is the CYP2C19 enzyme. The CYP2C19 gene is polymorphic, and the variation is common especially in the Asian population.CONTENT: CYP2C19 is responsible for the metabolism of various drugs, including proton pump inhibitors (PPIs) such as omeprazole and lansoprazole, psychotropic drugs including diazepam and imipramine, anticonvulsants such as phenobarbital and mephenytoin. and the recently most studied the anti-platelet drug, clopidogrel, and many others. Drugs metabolized predominantly by this enzyme like clopidogrel and PPIs might be much affected by the genotype status of CYP2C19. Clopidogrel is a pro-drug requiring a group of enzymes to convert to its active form, particularly the CYP2C19. PPIs are metabolized to its inactive metabolites mainly by CYP2C19 in the liver. Some PPIs are inhibitor of CYP2C19 enzymes, and interaction of PPIs and clopidogrel has been widely studied.SUMMARY: The association of CYP2C19 genotypes with the plasma level of active clopidogrel and platelet reactivity in individual taking this drug is well-established. Although conflicting results still exist for the association of CYP2C19 genotypes to the clinical outcomes of clopidogrel therapy, this effect seems to be consistent in patients receiving clopidogrel for coronary stents. Due to the interaction of certain PPIs and clopidogrel, the use of PPIs other than omeprazole is recommended, especially for patients taking dual anti platelet therapy of clopidogrel and aspirin.KEYWORDS: pharmacogenetics, CYP2C19, proton pump inhibitors, clopidogrel

Letter by Chyrchel et al Regarding Article, “Unexpected Effect of Proton Pump Inhibitors: Elevation of the Cardiovascular Risk Factor Asymmetric Dimethylarginine”

Ghebremariam et al1 brilliantly demonstrated that proton pump inhibitors (PPIs) inhibit dimethylarginine dimethylaminohydrolase, a key enzyme metabolizing the endogenous nitric oxide synthase antagonist asymmetrical dimethylarginine. This finding offers a novel mechanism for the putative ability of PPIs to attenuate benefits of antiplatelet agents, an effect initially attributed to the interaction of PPIs with clopidogrel activation by a hepatic enzyme (CYP2C19).2 …

Prevention of upper gastrointestinal haemorrhage: current controversies and clinical guidance

Acute upper gastrointestinal (GI) bleeding is a common medical emergency and associated with significant morbidly and mortality. The risk of bleeding from peptic ulceration and oesophagogastric varices can be reduced by appropriate primary and secondary preventative strategies. Helicobacter pylori eradication and risk stratification with appropriate gastroprotection strategies when used with antiplatelet drugs and nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in preventing peptic ulcer bleeding, whilst endoscopic screening and either nonselective beta blockade or endoscopic variceal ligation are effective at reducing the risk of variceal haemorrhage. For secondary prevention of variceal haemorrhage, the combination of beta blockade and endoscopic variceal ligation is more effective. Recent data on the possible interactions of aspirin and NSAIDs, clopidogrel and proton pump inhibitors (PPIs), and the increased risk of cardiovascular adverse events associated with all nonaspirin cyclo-oxygenase (COX) inhibitors have increased the complexity of choices for preventing peptic ulcer bleeding. Such choices should consider both the GI and cardiovascular risk profiles. In patients with a moderately increased risk of GI bleeding, a NSAID plus a PPI or a COX-2 selective agent alone appear equivalent but for those at highest risk of bleeding (especially those with previous ulcer or haemorrhage) the COX-2 inhibitor plus PPI combination is superior. However naproxen seems the safest NSAID for those at increased cardiovascular risk. Clopidogrel is associated with a significant risk of GI haemorrhage and the most recent data concerning the potential clinical interaction of clopidogrel and PPIs are reassuring. In clopidogrel-treated patients at highest risk of GI bleeding, some form of GI prevention is indicated.

A population-based case–control study: proton pump inhibition and risk of hip fracture by use of bisphosphonate

Studies on the risk of osteoporotic fractures related to the use of proton pump inhibitors (PPIs) have been inconsistent. One recent cohort study reported that there was an interaction between PPIs and bisphosphonates (BPs). Thus we performed a case-control study aimed at evaluating the risk of hip fractures related to PPIs and exploring the interaction between PPIs and BPs. A case-control study was performed using the Korean Health Insurance Review and Assessment Service database from 2005 January to 2006 June. The cases were all incident hip fractures identified from July 2005 to June 2006, and up to four controls were matched to each case by age, gender, and osteoporosis. Conditional logistic regression was used to calculate the adjusted odds ratio (aOR) and its 95 % confidence intervals. A total of 24,710 cases were identified and 98,642 controls were matched to the cases. The aOR and its 95 % CI of hip fractures related to the use of PPIs was 1.34 (95 % CI 1.24-1.44). When the study participants were stratified according to BP use, the aOR was 1.30 (95 % CI 1.19-1.42) in BP non-users, which was significantly different from the 1.71 (95 % CI 1.31-2.23) of BP users. Only BP users showed a decreasing tendency toward fracture risk as exposure to PPI became less recent, and a trend of increasing risk with increasing cumulative doses. Our results suggest that the mechanism for increased risk of hip fracture by PPIs may arise mainly from interaction of BP and PPIs.

Statements of the Malaysian Society of Gastroenterology &amp; Hepatology and the National Heart Association of Malaysia task force 2012 working party on the use of antiplatelet therapy and proton pump inhibitors in the prevention of gastrointestinal bleeding

The working party statements aim to provide evidence and guidelines to practising doctors on the use of antiplatelet therapy and proton pump inhibitors (PPIs) in patients with cardiovascular risk as well as those at risk of gastrointestinal (GI) bleeding. Balancing the GI and cardiovascular risk and benefits of antiplatelet therapy and PPIs may sometimes pose a significant challenge to doctors. Concomitant use of anti-secretory medications has been shown to reduce the risk of GI bleeding but concerns have been raised on the potential interaction of PPIs and clopidogrel. Many new data have emerged on this topic but some can be confusing and at times controversial. These statements examined the supporting evidence in four main areas: rationale for antiplatelet therapy, risk factors of GI bleeding, PPI-clopidogrel interactions and timing for recommencing antiplatelet therapy after GI bleeding, and made appropriate recommendations.

Clinical Significance of the Clopidogrel–Proton Pump Inhibitor Interaction After Peripheral Endovascular Intervention for Claudication

Despite numerous studies in the cardiology literature, the clinical impact of proton pump inhibitor (PPI) administration on the antiplatelet effect of clopidogrel remains controversial. The objective of this study is to evaluate the effects of concurrent PPI and clopidogrel administration on outcomes after percutaneous transluminal angioplasty and stenting (PTA&S) of the superficial femoral artery (SFA) for claudication. Retrospective review of a prospectively maintained database (2004-2010) identified patients undergoing PTA&S of the SFA for lifestyle-limiting claudication (Rutherford Class III). Statistical analysis included univariate comparison (Wilcoxon, chi-square) of demographics, lesion characteristics, complication rates, and outcome measures. Patency comparisons were made with Cox-PH multivariable models and Kaplan-Meier survival analysis. Totally, 109 limbs were treated in 103 patients. All were prescribed clopidogrel for 1 month; concurrent PPI use (+PPI) was identified after 42 (38.5%) interventions. There were no statistically significant differences in demographics, comorbidity prevalence, lesion length, degree of stenosis, or runoff associated with PPI use. There were no cases of early thrombosis in either group. There were more instances of patency loss (28 [50%] vs 21 [42%]; P = .40) in patients with +PPI, and a trend toward reduced primary patency that did not achieve statistical significance (P = .5). By multivariate analysis only TransAtlantic Inter-Society Consensus (TASC) D lesions were independent predictors of primary (hazards ratio [HR] = 4.366; [95% confidence interval (CI): 1.291-14.764; P = .018) and assisted patency loss (HR = 6.815 [1.181-39.327]; P = .032). The clinical significance of the clopidogrel-PPI interaction is a controversial topic that has been the subject of numerous studies in the cardiology literature. This is the first report to examine this medication interaction after peripheral intervention. While there is no apparent association between PPI coadministration with clopidogrel in this series, the high prevalence of PPI use among patients prescribed clopidogrel following peripheral intervention warrants ongoing attention to this purported medication interaction.

An insight into the Interaction between Clopidogrel and Proton Pump Inhibitors

Platelet activation and aggregation have been established as pivotal elements in the pathogenesis of atherosclerotic and ischemic diseases, including acute coronary syndromes. The difficulty of achieving optimal platelet inhibition remains a major constraint following dual-antiplatelet therapy, which can lead to a diminished response following initiation of clopidogrel therapy. Though the absolute mechanisms underlying clopidogrel resistance are controversial, a variety of responsible factors are recognized. Clopidogrel, being a prodrug, requires conversion to an active metabolite for its activity. This metabolism involves various cytochrome P450 (CYP) enzymes at different steps, and it is hypothesized that competitive inhibition of CYPs may contribute to clopidogrel resistance. Proton pump inhibitors (PPIs) are competitive inhibitors of CYPs that can attenuate the antiplatelet activity of clopidogrel, and this can lead to clopidogrel resistance. Available data from different clinical studies have postulated the possibility of a drug-drug interaction between clopidogrel and PPIs. PPIs differ somewhat in their pharmacokinetic properties like bioavaibility and affinity for CYP2C19. However it is not clear whether the proposed drug interaction of PPI with clopidogrel is same with all PPIs (i.e., a class effect) or it is limited to a subset of PPIs (i.e., a drug effect). This interaction needs further assessment with well designed prospective clinical trials, before any change in clinical practice should be considered. In this review, we attempt to evaluate the available evidence exploring drug interactions with PPIs as the underlying mechanism for the reduced antiplatelet effect of clopidogrel.

Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)

Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC50) were in the low micromolar range (3–36 µM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy.

Impact of proton pump inhibitors on efficacy of clopidogrel: Review of evidence

Clopidogrel is a prodrug which requires cytochrome P450 2C19 (CYP 2C19) enzyme for its conversion to an active thiol metabolite. Proton pump inhibitors (PPIs) inhibits enzyme CYP 2C19 interfering with the conversion of clopidogrel into its active metabolite. Studies document the possible interaction of clopidogrel and PPIs leading to a decrease in the antiplatelet efficacy of clopidogrel. A PubMed/MEDLINE database literature search was carried out and the bibliographies of found articles were checked for other relevant literature. Most retrospective cohort studies and studies using platelet markers found a significant association between PPI use especially omeprazole and decreased efficacy of clopidogrel while few comparative trials using clinical outcomes found no association between the same. Pantoprazole was not associated with the decrease in the antiplatelet efficacy of clopidogrel. Patients on dual antiplatelet therapy and/or with a history of gastrointestinal bleed will require gastroprotection in the form of PPIs. In such cases, pantoprazole should be the preferred PPI. Rabeprazole can be used as an alternative.

Gastroenterologists May Inadequately Counsel Patients About the Potential Interaction Between Proton Pump Inhibitors and Concomitant Clopidogrel Use

Purpose: Guidelines endorse the use of clopidogrel for patients who have acute coronary syndromes or percutaneous coronary intervention. Clopidogrel is a prodrug that needs to be activated by the CYP2C19 enzyme in the liver to its active metabolite, which inhibits platelet activity. Proton pump inhibitors may inhibit CYP2C19 decreasing the efficacy of clopidogrel and increasing the risk for reinfarction. It is uncertain if gastroenterologists counsel their patients about this potential interaction. This study evaluated the frequency of physician counseling of patients treated with clopidogrel and PPI regarding the potential drug interaction and risk of recurrent coronary events. Methods: A retrospective medical chart review of consecutive patients prescribed proton pump inhibitors (PPIs) with and without clopidogrel who were referred during a 6 month period to a university gastroenterology practice was conducted. Documentation of counseling regarding long-term PPI use as well as potential drug interaction of clopidogrel and PPIs was obtained. A database was created using Microsoft Excel. Patient anonymity was maintained. Statistical analysis was performed using Fischer's Exact test with significance set at p<0.05. The study was approved by the IRB. Results: The medical records of 2500 patients were reviewed. One hundred fifteen patients were identified as taking a PPI for a duration >1 month. The primary indications for PPI use were GERD (73.0%) and peptic ulcer disease (21.7%). Eleven of the 115 patients (9.6%) maintained on PPI were on concomitant clopidogrel. Thirty-three of 115 patients (28.7%) were counseled about potential adverse effects of long-term PPI use. None of the patients on PPI and clopidogrel were counseled about potential drug interactions. There was a significant difference in the rate at which patients on PPI are counseled about long-term PPI use as compared to PPI and clopidogrel interactions (p<0.03). Conclusion: Long-term PPI use in the United States is widespread for various clinical indications. Consequently, there is a high likelihood of concomitant clopidogrel and PPI use in patients with a history of acute coronary syndromes or prior percutaneous coronary stenting. This study revealed that there was suboptimal counseling about the potential effects of long-term PPI use and no counseling regarding the potential effect of concomitant PPI and clopidogrel use. As PPI use has been associated with an increased risk for recurrent coronary events in patients taking clopidogrel, it is important that physicians discuss the adverse effects of PPI therapy as well as the potential drug interaction.

Helicobacter pylori infection, chronic gastritis, and proton pump inhibitors.

The proton pump inhibitors (PPIs) omeprazole, lansoprazole, and pantoprazole are widely used as antisecretory drugs and, in association with antibiotics, for the treatment of Helicobacter pylori infections. PPIs possess antibacterial activity against H. pylori in vitro, and may also exert an anti-inflammatory effect by interfering with the cellular immune response to infection. Their antimicrobial activity is selective for H. pylori. Lansoprazole is the most effective, although its bactericidal activity is similar to that of omeprazole. Pantoprazole is the least effective. The mechanisms that account for the antibacterial effects of PPIs may depend on a structural similarity of PPIs to antibiotics which are active against H. pylori, on the inhibition of bacterial urease exerted by PPIs, or on the possible interaction of PPIs with bacterial ATPases that regulate the transmembrane ion flux. Recent studies have shown that PPIs have anti-inflammatory actions and can interfere with the host-bacteria interactions. Lansoprazole can bind to polymorphonuclear leukocytes that infiltrate the gastric mucosa colonized by H. pylori and can thus inhibit the oxidative burst of activated inflammatory cells. In an in vivo study, lansoprazole reduced the degree of activity of histologic gastritis independently of the presence of H. pylori. In another study, omeprazole was capable of inhibiting the cytotoxic activity of NK T cells. Investigation of PPI interactions with H. pylori activities and the cellular immune response to the infection may help us to understand the pathogenic mechanisms of H. pylori-associated diseases and enable clinicians to better treat them.

The interaction of proton pump inhibitors with cytochromes P450.

An understanding of the role of human cytochromes (CYPs) P450 in the metabolism of proton pump inhibitors (PPIs) is important in assuring the safety of these drugs. Species' differences in the metabolism of PPIs tend to overestimate the risk of some forms of toxicity in humans. Therefore, information on metabolism by human enzymes is essential for the prediction of drug interactions, or the lack of them. Although extrapolation from population mean data to the individual patient should be made with care, available data indicate that the use of PPIs, omeprazole, lansoprazole and particularly pantoprazole, should be relatively free of clinically-significant drug interactions. This finding may reflect the level of therapeutic dosages for PPIs, and their short elimination half-lives with respect to exposure to drug-metabolizing enzymes. Concern about low-grade induction of CYPIA-mediated procarcinogen metabolism suggests a need for vigilance on the long-term use of PPIs.