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      Pantoprazole Does not Affect Serum Trough Levels of Tacrolimus and Everolimus in Liver Transplant Recipients

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          Abstract

          Background: Liver transplant recipients are frequently treated with proton pump inhibitors. Drug interactions have been described especially with respect to omeprazole. Due to the lower binding capacity of pantoprazole to CYP2C19 this drug became preferred and became the most used proton pump inhibitor in Germany. The data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients a very scarce.

          Methods: The authors performed a single center analysis in liver transplant recipients on the effect of pantoprazole on the serum trough levels of different immunosuppressants. The trough levels were compared over a period of 1 year before and after start or stop of a continuous oral co-administration of 40 mg pantoprazole once daily.

          Results: The serum trough levels of tacrolimus ( n = 30), everolimus ( n = 7), or sirolimus ( n = 3) remain constant during an observation period of at least 1 year before and after co-administration of pantoprazole. None of the included patients needed a change of dosage of the observed immunosuppressants during the observation period.

          Conclusions: The oral co-administration of pantoprazole is safe in immunosuppressed liver transplant recipients according to the serum trough levels of tacrolimus, everolimus, and sirolimus. This analysis provides first data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients.

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          Most cited references33

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          Pharmacokinetic Drug Interaction Profiles of Proton Pump Inhibitors: An Update

          Proton pump inhibitors (PPIs) are used extensively for the treatment of gastric acid-related disorders, often over the long term, which raises the potential for clinically significant drug interactions in patients receiving concomitant medications. These drug–drug interactions have been previously reviewed. However, the current knowledge is likely to have advanced, so a thorough review of the literature published since 2006 was conducted. This identified new studies of drug interactions that are modulated by gastric pH. These studies showed the effect of a PPI-induced increase in intragastric pH on mycophenolate mofetil pharmacokinetics, which were characterised by a decrease in the maximum exposure and availability of mycophenolic acid, at least at early time points. Post-2006 data were also available outlining the altered pharmacokinetics of protease inhibitors with concomitant PPI exposure. New data for the more recently marketed dexlansoprazole suggest it has no impact on the pharmacokinetics of diazepam, phenytoin, theophylline and warfarin. The CYP2C19-mediated interaction that seems to exist between clopidogrel and omeprazole or esomeprazole has been shown to be clinically important in research published since the 2006 review; this effect is not seen as a class effect of PPIs. Finally, data suggest that coadministration of PPIs with methotrexate may affect methotrexate pharmacokinetics, although the mechanism of interaction is not well understood. As was shown in the previous review, individual PPIs differ in their propensities to interact with other drugs and the extent to which their interaction profiles have been defined. The interaction profiles of omeprazole and pantoprazole sodium (pantoprazole-Na) have been studied most extensively. Several studies have shown that omeprazole carries a considerable potential for drug interactions because of its high affinity for CYP2C19 and moderate affinity for CYP3A4. In contrast, pantoprazole-Na appears to have lower potential for interactions with other medications. Lansoprazole and rabeprazole also seem to have a weaker potential for interactions than omeprazole, although their interaction profiles, along with those of esomeprazole and dexlansoprazole, have been less extensively investigated. Only a few drug interactions involving PPIs are of clinical significance. Nonetheless, the potential for drug interactions should be considered when choosing a PPI to manage gastric acid-related disorders. This is particularly relevant for elderly patients taking multiple medications, or for those receiving a concomitant medication with a narrow therapeutic index.
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            Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19.

            The isoenzymes which catalyse the polymorphic hydroxylations of debrisoquine/sparteine and S-mephenytoin are cytochromes P450 2D6 and P450 2C19 (CYP2D6 and CYP2C19), respectively. CYP2D6 is involved in the stereospecific metabolism of several important groups of drugs, for example antiarrhythmics, antidepressants and neuroleptics. About 7% of Caucasians but only 1% of Orientals are poor metabolisers (PMs) of debrisoquine. The most common mutated allele CYP2D6B in Caucasian PMs is almost absent from their Oriental counterparts. On the other hand, the mean activity of CYP2D6 in Oriental extensive metabolisers (EMs) is lower than that in Caucasian EMs. This is due to the frequent distribution of a partially deficient CYP2D6 allele causing a Pro34-->Ser amino acid exchange in as many as 50% of Oriental alleles. This is the molecular genetic basis for slower metabolism of antidepressants and neuroleptics observed in Oriental compared with Caucasian people, and consequently for the lower dosages of these drugs used. While CYP2D6 catalyses the metabolism of lipophilic bases only, CYP2C19 is involved in the metabolism of acids (e.g. S-mephenytoin), bases (e.g. imipramine and omeprazole) and neutral drugs (e.g. diazepam). About 3% of Caucasians and 12 to 22% of Orientals are PMs of S-mephenytoin. Polymerase chain reaction-based genotyping techniques recently became available for the two CYP2C19 mutated alleles m1 and m2, which cause no enzyme to be expressed. M1 accounts for about 80% of the mutations responsible for the PM phenotypes in Caucasians, Oriental and Black people. Diazepam is partially demethylated by CYP2C19, and the high frequency of mutated alleles in Orientals is probably the reason why such populations have a slower metabolism and are treated with lower doses of diazepam than Caucasians. Omeprazole is to a major extent hydroxylated by CYP2C19, and there is an approximately 10-fold difference in oral clearance between EMs and PMs of S-mephenytoin. The separation of Caucasians from Orientals is fairly recent in the evolutionary process (40,000 to 60,000 years ago); the separation of Black from Caucasian/Oriental people occurred much earlier, about 150,000 years ago. As pronounced differences have been found between Caucasians and Orientals in the CYP2D6 and CYP2C19 enzymes, it might be expected that Black people will show even greater differences in this respect. Some studies have been performed with Black participants, but the picture is not clear. The mean CYP2D6 activity in Black EMs seems to be lower than that in Caucasian EMs and similar to that of Oriental EMs.(ABSTRACT TRUNCATED AT 400 WORDS)
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              Pharmacokinetic drug interaction profiles of proton pump inhibitors.

              Proton pump inhibitors are used extensively for the treatment of gastric acid-related disorders because they produce a greater degree and longer duration of gastric acid suppression and, thus, better healing rates, than histamine H(2) receptor antagonists. The need for long-term treatment of these disorders raises the potential for clinically significant drug interactions in patients receiving proton pump inhibitors and other medications. Therefore, it is important to understand the mechanisms for drug interactions in this setting. Proton pump inhibitors can modify the intragastric release of other drugs from their dosage forms by elevating pH (e.g. reducing the antifungal activity of ketoconazole). Proton pump inhibitors also influence drug absorption and metabolism by interacting with adenosine triphosphate-dependent P-glycoprotein (e.g. inhibiting digoxin efflux) or with the cytochrome P450 (CYP) enzyme system (e.g. decreasing simvastatin metabolism), thereby affecting both intestinal first-pass metabolism and hepatic clearance. Although interactions based on the change of gastric pH are a group-specific effect and thus may occur with all proton pump inhibitors, individual proton pump inhibitors differ in their propensities to interact with other drugs and the extent to which their interaction profiles have been defined. The interaction profiles of omeprazole and pantoprazole have been studied most extensively. A number of studies have shown that omeprazole carries a considerable potential for drug interactions, since it has a high affinity for CYP2C19 and a somewhat lower affinity for CYP3A4. In contrast, pantoprazole appears to have lower potential for interactions with other medications. Although the interaction profiles of esomeprazole, lansoprazole and rabeprazole have been less extensively investigated, evidence suggests that lansoprazole and rabeprazole seem to have a weaker potential for interactions than omeprazole. Although only a few drug interactions involving proton pump inhibitors have been shown to be of clinical significance, the potential for drug interactions should be taken into account when choosing a therapy for gastric acid-related disorders, especially for elderly patients in whom polypharmacy is common, or in those receiving a concomitant medication with a narrow therapeutic index.
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                Author and article information

                Contributors
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                19 November 2018
                2018
                : 5
                : 320
                Affiliations
                [1] 1Clinic for Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Georg-August-University , Goettingen, Germany
                [2] 2Liver Center Goettingen, University Medical Center Goettingen, Georg-August-University , Goettingen, Germany
                [3] 3Clinic for Anesthesiology, University Medical Center Goettingen, Georg-August-University , Goettingen, Germany
                [4] 4Clinic for General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Georg-August-University , Goettingen, Germany
                Author notes

                Edited by: Pedro M. Baptista, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Spain

                Reviewed by: Alberto Lué, Hospital Clínico Universitario Lozano Blesa, Spain; Taro Takami, Yamaguchi University, Japan

                *Correspondence: Harald Schwörer hschwoer@ 123456med.uni-goettingen.de

                This article was submitted to Gastroenterology, a section of the journal Frontiers in Medicine

                †These authors have contributed equally to this work

                Article
                10.3389/fmed.2018.00320
                6253821
                70feffe3-e817-4066-903b-ebd763020593
                Copyright © 2018 Bremer, Reinhardt, Sobotta, Hasselluhn, Lorf, Ellenrieder and Schwörer.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 August 2018
                : 30 October 2018
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 35, Pages: 5, Words: 3666
                Funding
                Funded by: Deutsche Forschungsgemeinschaft 10.13039/501100001659
                Categories
                Medicine
                Original Research

                immunosuppressive drugs,pantoprazole,serum trough levels,liver transplant recipients,tacrolimus,everolimus

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