<?xml version="1.0" encoding="UTF-8"?>
<!DOCTYPE article PUBLIC "-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" "journalpublishing.dtd">
<article article-type="research-article" dtd-version="2.3" xml:lang="EN" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">
<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Pharmacol.</journal-id>
<journal-title>Frontiers in Pharmacology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Pharmacol.</abbrev-journal-title>
<issn pub-type="epub">1663-9812</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="publisher-id">1352323</article-id>
<article-id pub-id-type="doi">10.3389/fphar.2024.1352323</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Pharmacology</subject>
<subj-group>
<subject>Clinical Trial</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Assessment of omeprazole and famotidine effects on the pharmacokinetics of tacrolimus in patients following kidney transplant&#x2013;randomized controlled trial</article-title>
<alt-title alt-title-type="left-running-head">Miedziaszczyk et al.</alt-title>
<alt-title alt-title-type="right-running-head">
<ext-link ext-link-type="uri" xlink:href="https://doi.org/10.3389/fphar.2024.1352323">10.3389/fphar.2024.1352323</ext-link>
</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Miedziaszczyk</surname>
<given-names>Mi&#x142;osz</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="corresp" rid="c001">&#x2a;</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1598991/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/conceptualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/data-curation/"/>
<role content-type="https://credit.niso.org/contributor-roles/formal-analysis/"/>
<role content-type="https://credit.niso.org/contributor-roles/funding-acquisition/"/>
<role content-type="https://credit.niso.org/contributor-roles/investigation/"/>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
<role content-type="https://credit.niso.org/contributor-roles/project-administration/"/>
<role content-type="https://credit.niso.org/contributor-roles/resources/"/>
<role content-type="https://credit.niso.org/contributor-roles/software/"/>
<role content-type="https://credit.niso.org/contributor-roles/validation/"/>
<role content-type="https://credit.niso.org/contributor-roles/visualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Karczewski</surname>
<given-names>Marek</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/funding-acquisition/"/>
<role content-type="https://credit.niso.org/contributor-roles/investigation/"/>
<role content-type="https://credit.niso.org/contributor-roles/resources/"/>
<role content-type="https://credit.niso.org/contributor-roles/Writing - review &#x26; editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Grabowski</surname>
<given-names>Tomasz</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
<role content-type="https://credit.niso.org/contributor-roles/Writing - review &#x26; editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wolc</surname>
<given-names>Anna</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>3</sup>
</xref>
<xref ref-type="aff" rid="aff4">
<sup>4</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/177548/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/formal-analysis/"/>
<role content-type="https://credit.niso.org/contributor-roles/Writing - review &#x26; editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Idasiak-Piechocka</surname>
<given-names>Ilona</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/conceptualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/funding-acquisition/"/>
<role content-type="https://credit.niso.org/contributor-roles/investigation/"/>
<role content-type="https://credit.niso.org/contributor-roles/resources/"/>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
<role content-type="https://credit.niso.org/contributor-roles/Writing - review &#x26; editing/"/>
</contrib>
</contrib-group>
<aff id="aff1">
<sup>1</sup>
<institution>Department of General and Transplant Surgery</institution>, <institution>Poznan University of Medical Sciences</institution>, <addr-line>Poznan</addr-line>, <country>Poland</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Department of Inorganic Chemistry</institution>, <institution>Medical University of Gdansk</institution>, <addr-line>Gdansk</addr-line>, <country>Poland</country>
</aff>
<aff id="aff3">
<sup>3</sup>
<institution>Department of Animal Science</institution>, <institution>Iowa State University</institution>, <addr-line>Ames</addr-line>, <addr-line>IA</addr-line>, <country>United States</country>
</aff>
<aff id="aff4">
<sup>4</sup>
<institution>Hy-Line International</institution>, <addr-line>Dallas Center</addr-line>, <addr-line>IA</addr-line>, <country>United States</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>
<bold>Edited by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/475836/overview">Hong Shen</ext-link>, Bristol Myers Squibb, United States</p>
</fn>
<fn fn-type="edited-by">
<p>
<bold>Reviewed by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/2422896/overview">Shuo Wang</ext-link>, University of Washington, United States</p>
<p>
<ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/1390100/overview">Huaijun Zhu</ext-link>, Nanjing Drum Tower Hospital, China</p>
<p>
<ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/338558/overview">Xiaomin Liang</ext-link>, Gilead, United States</p>
</fn>
<corresp id="c001">&#x2a;Correspondence: Mi&#x142;osz Miedziaszczyk, <email>m.miedziaszczyk@wp.pl</email>
</corresp>
</author-notes>
<pub-date pub-type="epub">
<day>04</day>
<month>04</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>15</volume>
<elocation-id>1352323</elocation-id>
<history>
<date date-type="received">
<day>23</day>
<month>01</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>21</day>
<month>03</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Miedziaszczyk, Karczewski, Grabowski, Wolc and Idasiak-Piechocka.</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Miedziaszczyk, Karczewski, Grabowski, Wolc and Idasiak-Piechocka</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>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.</p>
</license>
</permissions>
<abstract>
<p>Tacrolimus is metabolized in the liver with the participation of the CYP3A4 and CYP3A5 enzymes. Proton pump inhibitors are used in kidney transplant patients to prevent duodenal and gastric ulcer disease due to glucocorticoids. Omeprazole, unlike famotidine, is a substrate and inhibitor of the enzymes CYP2C19, CYP3A4, CYP3A5. The aim of this study was to compare the impact of omeprazole and famotidine on the pharmacokinetics of tacrolimus. A randomized, non-blinded study involving 22 stabilized adult kidney transplant patients was conducted. Patients received the standard triple immunosuppression regimen and omeprazole 20&#xa0;mg (n &#x3d; 10) or famotidine 20&#xa0;mg (n &#x3d; 12). The study material consisted of blood samples in which tacrolimus concentrations were determined using the Chemiluminescent Microparticle Immuno Assay method. A single administration of omeprazole increased tacrolimus concentrations at 2&#xa0;h (day 2) &#x3d; 11.90 &#xb1; 1.59&#xa0;ng/mL vs. 2&#xa0;h (day 1 &#x2014; no omeprazole administration) &#x3d; 9.40 &#xb1; 0.79&#xa0;ng/mL (<italic>p</italic> &#x3d; 0.0443). AUC<sub>0-6</sub> amounted to 63.07 &#xb1; 19.46&#xa0;ng &#xd7; h/mL (day 2) vs. 54.23 &#xb1; 10.48&#xa0;ng &#xd7; h/mL (day 1), (<italic>p</italic> &#x3d; 0.0295). AUC<sub>2-6</sub> amounted to 44.32 &#xb1; 11.51&#xa0;ng &#xd7; h/mL (day 2) vs. 38.68 &#xb1; 7.70&#xa0;ng &#xd7; h/mL (day 1), (<italic>p</italic> &#x3d; 0.0130). Conversely, no significant changes in values of pharmacokinetic parameters were observed for famotidine. Omeprazole significantly increases blood exposure of tacrolimus. The administration of famotidine instead of omeprazole seems safer for patients following kidney transplantation.</p>
<p>
<bold>Clinical Trial Registration:</bold> <ext-link ext-link-type="uri" xlink:href="http://clinicaltrials.gov">clinicaltrials.gov</ext-link>, identifier NCT05061303</p>
</abstract>
<kwd-group>
<kwd>omeprazole</kwd>
<kwd>famotidine</kwd>
<kwd>tacrolimus pharmacokinetics</kwd>
<kwd>kidney transplant</kwd>
<kwd>pharmacotherapy</kwd>
</kwd-group>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Drug Metabolism and Transport</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1">
<title>1 Introduction</title>
<p>Currently, the majority of immunosuppressive regimens employed after kidney transplantation include tacrolimus (<xref ref-type="bibr" rid="B7">Franco et al., 2019</xref>). Tacrolimus is an calcineurin inhibitor used to prevent rejection in allogeneic organ transplant recipients, such as kidney, liver, heart or lungs. It is a substrate for intestinal P-glycoprotein (<xref ref-type="bibr" rid="B13">Marfo et al., 2010</xref>). Tacrolimus is metabolized in the liver with the participation of the cytochrome P450 isoform CYP3A4 and CYP3A5 (CYP3A4, CYP3A5) (<xref ref-type="bibr" rid="B6">Floren et al., 1997</xref>; <xref ref-type="bibr" rid="B4">Christians et al., 1996</xref>), and is characterized by a narrow therapeutic window, dose-dependent toxicity and high inter-individual and intra-individual variability. Tacrolimus is a nephrotoxic drug. Additionally, tacrolimus blood concentrations require regular monitoring during therapy, which is referred to as therapeutic drug monitoring (<xref ref-type="bibr" rid="B3">Budde et al., 2022</xref>). It is recommended to maintain tacrolimus C<sub>0</sub> trough concentrations &#x3e;7&#xa0;ng/mL in the first year after kidney transplantation in patients with low immunological risk, treated concomitantly with mycophenolate mofetil and glucocorticoids in combination with basiliximab induction. For recipients with increased immunological risk, higher tacrolimus C<sub>0</sub> concentrations are recommended: 10&#x2013;20&#xa0;ng/mL during the first 2 months, then 5&#x2013;10&#xa0;ng/mL. In Poland, induction with basiliximab is not routinely used in kidney transplant recipients with low immunological risk, therefore national recommendations are different (<xref ref-type="bibr" rid="B13">Marfo et al., 2010</xref>). The 6-year survival of the kidney graft was over 88% for the tacrolimus C<sub>0</sub> concentration ranges: 5.0&#x2013;6.9&#xa0;ng/mL and 7.0&#x2013;8.9&#xa0;ng/mL in the first 3 years after transplantation, 87.5% for &#x2265;9&#xa0;ng/mL, 86.5% for the range of 4.0&#x2013;4.9&#xa0;ng/mL and only 82.6% for C<sub>0</sub> values &#x3c;4&#xa0;ng/mL. The process of chronic rejection is most effectively inhibited when tacrolimus concentrations are maintained within the C<sub>0</sub> range: 5.0&#x2013;8.9&#xa0;ng/mL (<xref ref-type="bibr" rid="B28">Susal and Dohler, 2019</xref>). Increased blood concentrations of tacrolimus may be affected by CYP3A4 substrates and inhibitors, resulting in adverse effects of this drug, particularly nephrotoxicity (<xref ref-type="bibr" rid="B15">Miedziaszczyk and Idasiak-Piechocka, 2023</xref>). Proton pump inhibitors (PPIs) are administered as a standard treatment method in kidney transplant patients in order to prevent duodenal and gastric ulcer disease due to pro-inflammatory effects of immunosuppressive agents use or infections (<xref ref-type="bibr" rid="B29">Takahashi et al., 2007</xref>; <xref ref-type="bibr" rid="B24">Ponticelli and Passerini, 2005</xref>; <xref ref-type="bibr" rid="B30">Telkes et al., 2011</xref>). Glucocorticoids represent one of the most frequently employed triple immunosuppression regimens following kidney transplantation. One of the PPIs is omeprazole, which is a substrate and inhibitor of the enzymes CYP2C19, CYP3A4, CYP3A5, and simultaneously a P-glycoprotein inhibitor (<xref ref-type="bibr" rid="B16">Moreau et al., 2006</xref>; <xref ref-type="bibr" rid="B21">Pauli-Magnus et al., 2001</xref>). CYP2C19 enzyme is primarily involved in the metabolism of omeprazole; however, upon saturation or in the event of a mutation in the CYP2C19 gene (in poor metabolizers), CYP3A4/5 emerges as the major enzyme participating in the elimination of omeprazole and, thus, may interact with tacrolimus (<xref ref-type="bibr" rid="B34">Zhao WFM. et al., 2012</xref>; <xref ref-type="bibr" rid="B9">Hosohata et al., 2009</xref>; <xref ref-type="bibr" rid="B12">Maguire et al., 2012</xref>; <xref ref-type="bibr" rid="B1">Boso et al., 2013</xref>). Therefore, it seems vital to administer medications with a similar gastro-protective effect, such as famotidine - an antagonist of H2 receptors that, contrary to omeprazole, are not substrates or inhibitors of the CYP3A4/5 enzyme. There are no studies in the available scientific literature comparing changes in tacrolimus concentrations in patients following kidney transplantation receiving concomitant omeprazole vs. receiving famotidine instead of omeprazole. Our study is the first to present results comparing the above-mentioned research groups. The potential impact of omeprazole on the pharmacokinetics of tacrolimus (<xref ref-type="bibr" rid="B7">Franco et al., 2019</xref>; <xref ref-type="bibr" rid="B6">Floren et al., 1997</xref>; <xref ref-type="bibr" rid="B4">Christians et al., 1996</xref>; <xref ref-type="bibr" rid="B3">Budde et al., 2022</xref>; <xref ref-type="bibr" rid="B29">Takahashi et al., 2007</xref>; <xref ref-type="bibr" rid="B16">Moreau et al., 2006</xref>; <xref ref-type="bibr" rid="B33">Zhao W. et al., 2012</xref>; <xref ref-type="bibr" rid="B9">Hosohata et al., 2009</xref>; <xref ref-type="bibr" rid="B12">Maguire et al., 2012</xref>; <xref ref-type="bibr" rid="B1">Boso et al., 2013</xref>; <xref ref-type="bibr" rid="B25">Sugimoto and Furuta, 2012</xref>; <xref ref-type="bibr" rid="B5">Dehbozorgi et al., 2018</xref>; <xref ref-type="bibr" rid="B20">Pascual et al., 2005</xref>; <xref ref-type="bibr" rid="B22">Peloso et al., 2014</xref>), may result in fluctuations in the blood concentrations, drug toxicity and, consequently, lead to the development of chronic rejection of the transplanted kidney. It is important to investigate omeprazole-tacrolimus interaction, as well as to explore neutral therapeutic substances to prevent gastrointestinal complications. The use of famotidine instead of omeprazole may prove a more beneficial and safer treatment option for renal transplant patients. Bearing in mind these observations, the aim of the study was to compare the effects of omeprazole and famotidine on the pharmacokinetics of tacrolimus in patients following kidney transplant.</p>
</sec>
<sec sec-type="materials|methods" id="s2">
<title>2 Materials and methods</title>
<p>The study, randomized, non-blinded, comprised 24 stabilized adult patients between 1&#x2013;12 months after kidney transplantation (NCT05061303), who received a kidney from a deceased donor. Inclusion criteria were time since kidney transplantation (1&#x2013;12 months after kidney transplantation) and standard immunosuppressive regimen (tacrolimus, mycophenolate mofetil, prednisone/methylprednisolone/deflazacort). In this group, 2 individuals withdrew their informed consent and were excluded from study. Each randomized patient was admitted to the Department of Nephrology, Transplantology and Internal Diseases of Poznan University of Medical Sciences for 2 days (48&#xa0;h). The study used the simple randomization method. One of the authors of the study (no the principal researcher) generated a randomized sequence for assigning patients to groups. The random component (computer-generated random numbers) was used in the sequence generation process. <xref ref-type="fig" rid="F1">Figure 1</xref> presented CONSORT flow chart. No participant changed the group during the study. Standard laboratory tests (creatinine, estimated glomerular filtration rate (eGFR), complete blood count, proteinuria, erythrocyturia) were performed during the first 2&#xa0;days of participation in the study. In addition, the glomerular filtration rate (GFR) was calculated for each patient using The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation to estimate GFR. The baseline characteristics of the study groups are presented in <xref ref-type="table" rid="T1">Table 1</xref>. Patients received orally the standard, most commonly administered triple immunosuppressive regimen: tacrolimus, mycophenolate mofetil, prednisone/methylprednisolone/deflazacort and orally: omeprazole 20&#xa0;mg (group I), or famotidine 20&#xa0;mg (group II) depending on the random classification to the groups. Patients received tacrolimus once daily in the form of tacrolimus monohydrate prolonged-release tablets (Envarsus<sup>&#xae;</sup>, Chiesi Farmaceutici), registration numbers: EU/1/14/935/00, EU/1/14/935/004, EU/1/14/935/006, EU/1/14/935/007 or in the form of tacrolimus monohydrate prolonged-release hard capsules (Advagraf<sup>&#xae;</sup>, Astellas Pharma Europe), registration numbers: EU/1/07/387/001, EU/1/07/387/003, EU/1/07/387/011, EU/1/07/387/007. Notably, patients were continuously treated with tacrolimus prior to entering the study. All patients before the start of the study achieved tacrolimus steady state. The material for the study involved blood samples in which tacrolimus concentrations were determined at the following time points: 0&#xa0;h, 2&#xa0;h, 6&#xa0;h, 12&#xa0;h after drug administration, when no omeprazole/famotidine was administered, and then the following day after receiving gastro-protective medications at the same time points, except for 12&#xa0;h time point. Since the elimination half-life of omeprazole in the body is shorter than an hour, no significant effect of omeprazole on tacrolimus metabolism was expected after a few hours, therefore, tacrolimus concentrations were not assessed at the 12&#xa0;h time point during the second day of hospitalization to avoid exposed patients to additional blood donation (Summary of Product Characteristics ofa) (Summary of Product Characteristics ofb). The results were used to obtain the values of pharmacokinetic parameters and statistical evaluation. A graphical representation of the research methodology is presented in <xref ref-type="fig" rid="F2">Figure 2</xref>. No study-related adverse events were reported by patients, physicians, medical staff, or others during the study.</p>
<fig id="F1" position="float">
<label>FIGURE 1</label>
<caption>
<p>CONSORT flow chart.</p>
</caption>
<graphic xlink:href="fphar-15-1352323-g001.tif"/>
</fig>
<table-wrap id="T1" position="float">
<label>TABLE 1</label>
<caption>
<p>The characteristics of the study groups. The values are provided as the number of patients (n) or as mean &#xb1; SD.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">Characteristic parameter</th>
<th align="center">Group I</th>
<th align="center">Group II</th>
<th align="center">Shapiro-Wilk test (<italic>p</italic>-value)</th>
<th align="center">95% Cl</th>
<th align="center">t-test for non-dependent groups (<italic>p</italic>-value)</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">Gender (n; men/women)</td>
<td align="center">5/5</td>
<td align="center">10/2</td>
<td align="center">-</td>
<td align="center">-</td>
<td align="center">-</td>
</tr>
<tr>
<td align="left">Age (years)</td>
<td align="center">41 &#xb1; 15</td>
<td align="center">50 &#xb1; 9</td>
<td align="center">
<italic>p</italic> &#x3d; 0.4999</td>
<td align="center">&#x2212;2.3895 to 19.7228</td>
<td align="center">
<italic>p</italic> &#x3d; 0.1177</td>
</tr>
<tr>
<td align="left">Body Mass Index (kg/m<sup>2</sup>)</td>
<td align="center">23.30 &#xb1; 3.33</td>
<td align="center">26.65 &#xb1; 5.08</td>
<td align="center">
<italic>p</italic> &#x3d; 0.2699</td>
<td align="center">&#x2212;0.5621 to 7.2561</td>
<td align="center">
<italic>p</italic> &#x3d; 0.0893</td>
</tr>
<tr>
<td rowspan="2" align="left">systolic/diastolic blood pressure (SBP/DBP) (mmHg) arterial hypertension</td>
<td rowspan="2" align="center">141.30 &#xb1; 21.50/90.10 &#xb1; 11.78 (n &#x3d; 6)</td>
<td rowspan="2" align="center">146.73 &#xb1; 20.18/92.45 &#xb1; 13.58 (n &#x3d; 6)</td>
<td align="center">SBP <italic>p</italic> &#x3d; 0.5590</td>
<td align="center">SBP -13.6108 to 24.4654</td>
<td align="center">SBP <italic>p</italic> &#x3d; 0.5578</td>
</tr>
<tr>
<td align="center">DBP <italic>p</italic> &#x3d; 0.9429</td>
<td align="center">DBP -9.3148 to 14.0238</td>
<td align="center">DBP <italic>p</italic> &#x3d; 0.6775</td>
</tr>
<tr>
<td rowspan="3" align="left">Creatinine concentration (mg/dL)</td>
<td align="center">Q1: 1.12</td>
<td align="center">Q1: 1.37</td>
<td rowspan="3" align="center">
<bold>p &#x3d; 0.0331</bold>
</td>
<td rowspan="3" align="center">-</td>
<td rowspan="3" align="center">
<italic>p</italic> &#x3d; 0.0503<xref ref-type="table-fn" rid="Tfn1">
<sup>1</sup>
</xref>
</td>
</tr>
<tr>
<td align="center">Q2: 1.31</td>
<td align="center">Q2: 1.50</td>
</tr>
<tr>
<td align="center">Q3: 1.38</td>
<td align="center">Q3: 1.87</td>
</tr>
<tr>
<td align="left">Glomerular Filtration Rate [The Chronic Kidney Disease - Epidemiology Collaboration] (mL/min/1,73&#xa0;m<sup>2)</sup>
</td>
<td align="center">67.80 &#xb1; 25.87</td>
<td align="center">51.75 &#xb1; 14.11</td>
<td align="center">
<italic>p</italic> &#x3d; 0.4628</td>
<td align="center">&#x2212;34.1503 to 2.0503</td>
<td align="center">
<italic>p</italic> &#x3d; 0.0792</td>
</tr>
<tr>
<td align="left">Tacrolimus daily dose (mg/kg)</td>
<td align="center">0.0611 &#xb1; 0.0381</td>
<td align="center">0.0376 &#xb1; 0.0162</td>
<td align="center">
<italic>p</italic> &#x3d; 0.0925</td>
<td align="center">&#x2212;0.0516 to 0.0047</td>
<td align="center">
<italic>p</italic> &#x3d; 0.0948<sup>2</sup>
</td>
</tr>
<tr>
<td align="left">Proteinuria (n)</td>
<td align="center">1</td>
<td align="center">5</td>
<td align="center">-</td>
<td align="center">-</td>
<td align="center">-</td>
</tr>
<tr>
<td align="left">Erythrocyturia (n)</td>
<td align="center">0</td>
<td align="center">2</td>
<td align="center">-</td>
<td align="center">-</td>
<td align="center">-</td>
</tr>
<tr>
<td align="left">Cytomegalovirus (n)</td>
<td align="center">3</td>
<td align="center">1</td>
<td align="center">-</td>
<td align="center">-</td>
<td align="center">-</td>
</tr>
<tr>
<td align="left">BK virus (n)</td>
<td align="center">0</td>
<td align="center">1</td>
<td align="center">-</td>
<td align="center">-</td>
<td align="center">-</td>
</tr>
<tr>
<td align="left">Anaemia (n)</td>
<td align="center">1</td>
<td align="center">3</td>
<td align="center">-</td>
<td align="center">-</td>
<td align="center">-</td>
</tr>
<tr>
<td align="center">the mean C<sub>0</sub>/D ratio (ng/mL&#x2a;1/mg)</td>
<td align="center">2.02 &#xb1; 1.14</td>
<td align="center">2.49 &#xb1; 0.76</td>
<td align="center">
<italic>p</italic> &#x3d; 0.4425</td>
<td align="center">&#x2212;0.2471 to 1.1338</td>
<td align="center">
<italic>p</italic> &#x3d; 0.1694</td>
</tr>
<tr>
<td align="center">poor metabolizers (n)</td>
<td align="center">5</td>
<td align="center">10</td>
<td align="center">-</td>
<td align="center">-</td>
<td align="center">-</td>
</tr>
<tr>
<td align="center">intermediate metabolizers (n)</td>
<td align="center">3</td>
<td align="center">2</td>
<td align="center">-</td>
<td align="center">-</td>
<td align="center">-</td>
</tr>
<tr>
<td align="center">ultra-rapid metabolizers (n)</td>
<td align="center">2</td>
<td align="center">0</td>
<td align="center">-</td>
<td align="center">-</td>
<td align="center">-</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>1&#x2014;the Mann-Whitney U test.</p>
</fn>
<fn>
<p>2&#x2014;the Welch&#x2019;s t-test.</p>
</fn>
<fn>
<p>Values in bold are statistically significant.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<fig id="F2" position="float">
<label>FIGURE 2</label>
<caption>
<p>The graphic representation of the study methodology. TAC - patients receiving tacrolimus alone on the first day of the study, TAC &#x2b; OM&#x2014;patients receiving tacrolimus together with omeprazole on the second day of the study, TAC &#x2b; FA&#x2014;patients receiving tacrolimus together with omeprazole on the second day of the study.</p>
</caption>
<graphic xlink:href="fphar-15-1352323-g002.tif"/>
</fig>
<p>In order to establish the tacrolimus metabolism rate in the patients, the blood concentration normalized by the dose (C/D ratio) was calculated. The C<sub>0</sub>/D ratio can be calculated by dividing the tacrolimus pre-dose concentration (C<sub>0</sub>) by the corresponding daily tacrolimus dose (D). In the presented study, the authors used the scale suggested by Th&#xf6;lking G. et al. If the C/D ratio was 1.05&#x2013;1.54&#xa0;ng/mL&#x2a;1/mg, the patients were classified as intermediate metabolizers. The fast metabolizers group included patients with a C/D ratio of &#x3c;1.05&#xa0;ng/mL&#x2a;1/mg, whereas if the aforementioned ratio was &#x2265;1.55&#xa0;ng/mL&#x2a;1/mg, the participants were described as slow metabolizers (<xref ref-type="bibr" rid="B31">Tholking et al., 2014</xref>). The results are presented in <xref ref-type="table" rid="T1">Table 1</xref>.</p>
<sec id="s2-1">
<title>2.1 Chemiluminescent microparticle immuno assay (CMIA)</title>
<p>Tacrolimus concentrations were determined using CMIA, by means of Alinity i analyser (<xref ref-type="bibr" rid="B14">Mei et al., 2018</xref>). Samples were stored frozen (&#x2212;10&#xb0;C or below) for no longer than 6 months. Each sample was thoroughly mixed prior to determining concentration, and 200&#xa0;&#x3bc;L of each sample was pipetted into a centrifuge tube. Subsequently, the dispenser was filled with the appropriate volume of ARCHITECT Tacrolimus Whole Blood Precipitation Reagent, followed by the removal of air bubbles from the dispenser. 200&#xa0;&#x3bc;L of ARCHITECT Tacrolimus Whole Blood Precipitation Reagent was added to the contents of the first centrifuge tube. Each individual tube was capped, mixed immediately after adding the reagent and centrifuged for 5&#x2013;10&#xa0;s. The tubes were then centrifuged again for 4&#xa0;min. Each tube was uncapped and the supernatant was decanted (poured off) into a Graft Pre-Treatment Tube. They were then vortexed for 5&#x2013;10&#xa0;s and assayed for the concentrations of tacrolimus.</p>
<p>Calibration was performed in duplicate samples by testing Calibrators A, B, C, D, E and F. Control samples were prepared by mixing 150&#xa0;&#x3bc;L of the patient sample and 150&#xa0;&#x3bc;L of ARCHITECT Tacrolimus Calibrator A. One sample for each control level was tested once every 24&#xa0;h as a quality control test. The analyst evaluating tacrolimus concentrations had no group assignment information.</p>
</sec>
<sec id="s2-2">
<title>2.2 Pharmacokinetic evaluation</title>
<p>Pharmacokinetic analysis of tacrolimus concentrations were determined by non-compartmental analysis. Phoenix WinNonlin 8.1 (Certara LC) software was used to calculate the pharmacokinetic parameters. The following parameters were calculated: AUC<sub>0-6</sub>&#x2014;a fraction of the area under the concentration-time curve between 0&#xa0;h and 6&#xa0;h; AUC&#x2a;<sub>0&#x2013;6</sub>&#x2014;a fraction of the area under the concentration-time curve between 0&#xa0;h and 6&#xa0;h normalized by the dose; AUC<sub>2-6</sub>&#x2014;a fraction of the area under the concentration-time curve between 2&#xa0;h and 6&#xa0;h; AUC&#x2a;<sub>2&#x2013;6</sub>&#x2014;a fraction of the area under the concentration-time curve between 2&#xa0;h and 6&#xa0;h normalized by the dose; C<sub>max</sub>&#x2013;the peak concentrations in the first and second day.</p>
</sec>
<sec id="s2-3">
<title>2.3 Statistical analysis</title>
<p>Statistical analysis was performed separately in group I and separately in group II. The values of pharmacokinetic parameters were compared for tacrolimus concentrations without the administration of omeprazole (group I) or famotidine (group II) vs. together with omeprazole or famotidine. The Shapiro-Wilk test was used to verify whether the results of differences in pairs of pharmacokinetic parameters were normally distributed. For normal distribution variables (<italic>p</italic> &#x3e; 0.05), the paired Student&#x2019;s t-test was applied to estimate the significance of differences between the two analysed groups. The parameters which were significantly different from the normal distribution (<italic>p</italic> &#x3c; 0.05) were analysed using the paired Wilcoxon signed-rank test.</p>
<p>The statistical analysis of the baseline values of the study groups was also performed. The Shapiro-Wilk test was used to verify whether the results of differences in pairs of pharmacokinetic parameters were normally distributed. For normal distribution variables (<italic>p</italic> &#x3e; 0.05), the non-paired Student&#x2019;s t-test was applied to estimate the significance of differences between the two analysed groups. The parameters which were significantly different from the normal distribution (<italic>p</italic> &#x3c; 0.05) were analysed using the Mann-Whitney U test. For normal distribution variables (<italic>p</italic> &#x3e; 0.05), the Welch&#x2019;s t-test was applied to estimate the significance of differences between the two analysed groups for unequal variances. F test was used to compare the variances between study groups.</p>
<p>The analysis was performed using UNIVARIATE procedure of SAS (SAS Institute Inc. 2002&#x2013;2012. The SAS System for Windows version 9.4. (Cary, NC, USA).</p>
</sec>
</sec>
<sec sec-type="results" id="s3">
<title>3 Results</title>
<p>The arithmetic mean blood tacrolimus concentrations after a single oral administration to the omeprazole and famotidine groups are shown in <xref ref-type="fig" rid="F3">Figure 3</xref>. The main pharmacokinetic parameters are summarized in <xref ref-type="table" rid="T2">Table 2</xref> and <xref ref-type="table" rid="T3">Table 3</xref>. Omeprazole significantly increased tacrolimus AUC<sub>0-6</sub> by 16.30% (<italic>p</italic> &#x3d; 0.0295), AUC<sub>0-6</sub> normalized by the dose by 12.88% (<italic>p</italic> &#x3d; 0.0300) and AUC<sub>2-6</sub> by 14.58% (<italic>p</italic> &#x3d; 0.0130) (<xref ref-type="fig" rid="F4">Figure 4</xref>), AUC<sub>2-6</sub> normalized by the dose by 12.74% (<italic>p</italic> &#x3d; 0.0109). In order to assess whether the difference in the daily dose of tacrolimus between the group receiving omeprazole and the group receiving famotidine affects the obtained study results, dose normalization was used. The obtained results do not lead to different conclusions than those without dose normalization. After administration of omeprazole and tacrolimus, the C<sub>2h</sub> value increased by 26.60% (<italic>p</italic> &#x3d; 0.0443). There were no significant differences after administration of omeprazole compared to the previous day when this drug was not administered in the following pharmacokinetic parameters of tacrolimus: C<sub>max</sub> (<italic>p</italic> &#x3d; 0.0955), C<sub>0</sub> (<italic>p</italic> &#x3d; 0.5876), C<sub>6</sub> (<italic>p</italic> &#x3d; 0.6409). Famotidine administration did not result in statistically significant pharmacokinetic parameters: C<sub>max</sub> (<italic>p</italic> &#x3d; 0.7199), C<sub>0</sub> (<italic>p</italic> &#x3d; 0.3394), C<sub>2</sub> (<italic>p</italic> &#x3d; 0.4344), C<sub>6</sub> (<italic>p</italic> &#x3d; 0.7374), AUC<sub>2-6</sub> (<italic>p</italic> &#x3d; 0.3910), AUC<sub>2-6</sub> normalized by the dose (<italic>p</italic> &#x3d; 0.3146), AUC<sub>0-6</sub> (<italic>p</italic> &#x3d; 0.3277), AUC<sub>0-6</sub> normalized by the dose (<italic>p</italic> &#x3d; 0.2438).</p>
<fig id="F3" position="float">
<label>FIGURE 3</label>
<caption>
<p>The concentration-time profiles of tacrolimus in patients receiving omeprazole (OM) or famotidine (FA). TAC - patients receiving tacrolimus alone on the first day of the study, TAC &#x2b; OM - patients receiving tacrolimus together with omeprazole on the second day of the study, TAC &#x2b; FA&#x2014;patients receiving tacrolimus together with omeprazole on the second day of the study. The dots on the figure define the mean values, the whiskers represent standard deviation values. The whiskers ending with a triangle refer to the TAC group (no FA) and then TAC &#x2b; FA. The whiskers ending with a line refer to the TAC group (no OM) and then TAC &#x2b; OM.</p>
</caption>
<graphic xlink:href="fphar-15-1352323-g003.tif"/>
</fig>
<table-wrap id="T2" position="float">
<label>TABLE 2</label>
<caption>
<p>The pharmacokinetic parameters of tacrolimus without and with coadministration of omeprazole 20&#xa0;mg (OM).</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="center">Pharmacokinetic parameters</th>
<th align="center">no OM (day 1)</th>
<th align="center">OM (day 2)</th>
<th align="center">Shapiro-Wilk test (<italic>p</italic>-value)</th>
<th align="center">95% Cl</th>
<th align="center">t-test for dependent groups (<italic>p</italic>-value)</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="center">C<sub>max</sub> (ng/mL)</td>
<td align="center">11.22 &#xb1; 2.34</td>
<td align="center">13.07 &#xb1; 4.30</td>
<td align="center">
<italic>p</italic> &#x3d; 0.3013</td>
<td align="center">&#x2212;0.3973 to &#x2212;4.0973</td>
<td align="center">0.0955</td>
</tr>
<tr>
<td align="center">C<sub>0</sub> (ng/mL)</td>
<td align="center">6.15 &#xb1; 2.12</td>
<td align="center">6.85 &#xb1; 3.76</td>
<td align="center">
<italic>p</italic> &#x3d; 0.0778</td>
<td align="center">&#x2212;2.1158 to 3.5158</td>
<td align="center">0.5876</td>
</tr>
<tr>
<td align="center">C<sub>2</sub> (ng/mL)</td>
<td align="center">9.40 &#xb1; 2.50</td>
<td align="center">11.90 &#xb1; 5.03</td>
<td align="center">
<italic>p</italic> &#x3d; 0.7298</td>
<td align="center">0.0786 to 4.9214</td>
<td align="center">
<bold>0.0443</bold>
</td>
</tr>
<tr>
<td align="center">C<sub>6</sub> (ng/mL)</td>
<td align="center">9.94 &#xb1; 3.03</td>
<td align="center">10.26 &#xb1; 1.99</td>
<td align="center">
<italic>p</italic> &#x3d; 0.4530</td>
<td align="center">&#x2212;1.1801 to 1.8201</td>
<td align="center">0.6409</td>
</tr>
<tr>
<td align="center">AUC<sub>0-6</sub> (ng &#xd7; h/mL)</td>
<td align="center">54.23 &#xb1; 10.48</td>
<td align="center">63.07 &#xb1; 19.46</td>
<td align="center">
<italic>p</italic> &#x3d; 0.5495</td>
<td align="center">&#x2212;15.8264 to 27.8264</td>
<td align="center">
<bold>0.0295</bold>
</td>
</tr>
<tr>
<td align="center">AUC<xref ref-type="table-fn" rid="Tfn1">
<sup>a</sup>
</xref>
<sub>0&#x2013;6</sub>
</td>
<td rowspan="2" align="center">1158.<xref ref-type="table-fn" rid="Tfn1">
<sup>a</sup>
</xref>5 &#xb1; 556.93</td>
<td rowspan="2" align="center">1308.01 &#xb1; 595.19</td>
<td rowspan="2" align="center">
<italic>p</italic> &#x3d; 0.5489</td>
<td rowspan="2" align="center">18.0754 to 280.3968</td>
<td rowspan="2" align="center">
<bold>0.0300</bold>
</td>
</tr>
<tr>
<td align="center">&#x2003;((ng &#xd7; h/mL)/(mg/kg))</td>
</tr>
<tr>
<td align="center">AUC<sub>2-6</sub>
</td>
<td rowspan="2" align="center">38.68 &#xb1; 7.70</td>
<td rowspan="2" align="center">44.32 &#xb1; 11.51</td>
<td rowspan="2" align="center">
<italic>p</italic> &#x3d; 0.7501</td>
<td rowspan="2" align="center">1.5050 to 9.7750</td>
<td rowspan="2" align="center">
<bold>0.0130</bold>
</td>
</tr>
<tr>
<td align="center">&#x2003;(ng &#xd7; h/mL)</td>
</tr>
<tr>
<td align="center">AUC<xref ref-type="table-fn" rid="Tfn1">
<sup>a</sup>
</xref>
<sub>2&#x2013;6</sub>
</td>
<td rowspan="2" align="center">832.98 &#xb1; 415.81</td>
<td rowspan="2" align="center">939.13 &#xb1; 453.89</td>
<td rowspan="2" align="center">
<italic>p</italic> &#x3d; 0.8026</td>
<td rowspan="2" align="center">30.9855 to 181.3068</td>
<td rowspan="2" align="center">
<bold>0.0109</bold>
</td>
</tr>
<tr>
<td align="center">&#x2003;((ng &#xd7; h/mL)/(mg/kg))</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="Tfn1">
<label>
<sup>a</sup>
</label>
<p>the area under the concentration-time curve normalized by the dose.</p>
</fn>
<fn>
<p>Values in bold are statistically significant.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T3" position="float">
<label>TABLE 3</label>
<caption>
<p>The pharmacokinetic parameters of tacrolimus without and with coadministration of famotidine 20&#xa0;mg (FA).</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="center">Pharmacokinetic parameters</th>
<th align="center">no FA (day 1)</th>
<th align="center">FA (day 2)</th>
<th align="center">Shapiro-Wilk test (<italic>p</italic>-value)</th>
<th align="center">95% Cl</th>
<th align="center">t-test for dependent groups (<italic>p</italic>-value)</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="center">C<sub>max</sub> (ng/mL)</td>
<td align="center">12.68 &#xb1; 4.39</td>
<td align="center">13.05 &#xb1; 4.17</td>
<td align="center">
<italic>p</italic> &#x3d; 0.5547</td>
<td align="center">&#x2212;1.7022 to 2.3856</td>
<td align="center">0.7199</td>
</tr>
<tr>
<td rowspan="3" align="center">C<sub>0h</sub> (ng/mL)</td>
<td align="center">Q1: 5.25</td>
<td align="center">Q1: 5.60</td>
<td rowspan="3" align="center">
<bold>p &#x3d; 0.0345</bold>
</td>
<td rowspan="3" align="center">-</td>
<td rowspan="3" align="center">0.3394&#x5e;</td>
</tr>
<tr>
<td align="center">Q2: 6.50</td>
<td align="center">Q2: 7.30</td>
</tr>
<tr>
<td align="center">Q3: 8.80</td>
<td align="center">Q3: 7.95</td>
</tr>
<tr>
<td align="center">C<sub>2</sub> (ng/mL)</td>
<td align="center">10.26 &#xb1; 4.64</td>
<td align="center">10.98 &#xb1; 4.27</td>
<td align="center">
<italic>p</italic> &#x3d; 0.0927</td>
<td align="center">&#x2212;1.2420 to 2.6920</td>
<td align="center">0.4344</td>
</tr>
<tr>
<td align="center">C<sub>6</sub> (ng/mL)</td>
<td align="center">10.75 &#xb1; 3.16</td>
<td align="center">11.04 &#xb1; 3.53</td>
<td align="center">
<italic>p</italic> &#x3d; 0.2040</td>
<td align="center">&#x2212;1.5748 to 2.1582</td>
<td align="center">0.7374</td>
</tr>
<tr>
<td align="center">AUC<sub>0-6</sub>
</td>
<td rowspan="2" align="center">59.15 &#xb1; 16.60</td>
<td rowspan="2" align="center">62.07 &#xb1; 15.92</td>
<td rowspan="2" align="center">
<italic>p</italic> &#x3d; 0.8709</td>
<td rowspan="2" align="center">&#x2212;3.3504 to 9.1838</td>
<td rowspan="2" align="center">0.3277</td>
</tr>
<tr>
<td align="center">&#x2003;(ng &#xd7; h/mL)</td>
</tr>
<tr>
<td align="center">AUC<xref ref-type="table-fn" rid="Tfn2">
<sup>a</sup>
</xref>
<sub>0&#x2013;6</sub>
</td>
<td rowspan="2" align="center">1677.84 &#xb1; 358.32</td>
<td rowspan="2" align="center">1784.71 &#xb1; 447.89</td>
<td rowspan="2" align="center">
<italic>p</italic> &#x3d; 0.7590</td>
<td rowspan="2" align="center">&#x2212;84.0925 to 297.8647</td>
<td rowspan="2" align="center">0.2437</td>
</tr>
<tr>
<td align="center">&#x2003;((ng &#xd7; h/mL)/(mg/kg))</td>
</tr>
<tr>
<td align="center">AUC<sub>2-6</sub> (ng &#xd7; h/mL)</td>
<td align="center">42.02 &#xb1; 11.54</td>
<td align="center">44.05 &#xb1; 11.28</td>
<td align="center">
<italic>p</italic> &#x3d; 0.7966</td>
<td align="center">&#x2212;2.9789 to 7.0456</td>
<td align="center">0.3910</td>
</tr>
<tr>
<td align="center">AUC<xref ref-type="table-fn" rid="Tfn2">
<sup>a</sup>
</xref>
<sub>2&#x2013;6</sub>
</td>
<td rowspan="2" align="center">1196.79 &#xb1; 279.50</td>
<td rowspan="2" align="center">1268.57 &#xb1; 329.31</td>
<td rowspan="2" align="center">
<italic>p</italic> &#x3d; 0.9537</td>
<td rowspan="2" align="center">&#x2212;78.1345 to 221.6834</td>
<td rowspan="2" align="center">0.3146</td>
</tr>
<tr>
<td align="center">&#x2003;((ng &#xd7; h/mL)/(mg/kg))</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="Tfn2">
<label>
<sup>a</sup>
</label>
<p>the area under the concentration-time curve normalized by the dose &#x5e; - the paired Wilcoxon signed-rank test.</p>
</fn>
<fn>
<p>Values in bold are statistically significant.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<fig id="F4" position="float">
<label>FIGURE 4</label>
<caption>
<p>The area under the concentration-time curve between 2&#xa0;h and 6&#xa0;h (AUC<sub>2-6</sub>) in patients receiving omeprazole. The AUC<sub>2-6</sub> values for patients taking tacrolimus without omeprazole are shown on the left. The AUC<sub>2-6</sub> values in patients taking tacrolimus and omeprazole concomitantly are shown on the right. The lower side of the box is defined by the first quartile, the upper side by the third quartile. The horizontal line inside the box represents the median value. The upper end of the line is the highest value in the group, while the lower end of the line is the lowest value.</p>
</caption>
<graphic xlink:href="fphar-15-1352323-g004.tif"/>
</fig>
</sec>
<sec sec-type="discussion" id="s4">
<title>4 Discussion</title>
<p>In our study, patients receiving omeprazole showed significantly higher tacrolimus concentrations than the participants without OM therapy (<xref ref-type="table" rid="T2">Table 2</xref>). Nevertheless, the addition of famotidine to pharmacotherapy instead of omeprazole did not result in any significant changes in tacrolimus blood concentrations. Given that both tacrolimus and omeprazole are metabolised by the CYP3A4 isoform of the cytochrome P450 group, there is a potential for drug-drug interactions through enzyme competition. In the available sources, a case report was found which corresponded to the results obtained in our study.</p>
<p>Takayashi K et al. (<xref ref-type="bibr" rid="B29">Takahashi et al., 2007</xref>) presented a case of a Japanese patient (32 years old) following kidney transplantation where a change in the concentration of tacrolimus in the blood was observed after replacing ranitidine with omeprazole. Immunosuppressive treatment included tacrolimus, mycophenolate mofetil, and prednisolone. On the post-transplant day 17, the trough concentration of tacrolimus was 12.5&#xa0;ng/mL with a daily oral dose of 17&#xa0;mg. Subsequently, on day 18, orally administered ranitidine was changed to intravenous omeprazole for the management of peptic ulcers. With the initiation of omeprazole treatment, tacrolimus trough levels abruptly increased to 30.0&#xa0;ng/mL on the post-transplant day 19. Despite tacrolimus dose reductions (from 17 to 9&#xa0;mg/day), tacrolimus trough levels remained above 15&#xa0;ng/mL. Furthermore, omeprazole was replaced with oral rabeprazole (10&#xa0;mg/day) on day 21. After switching to rabeprazole, blood concentrations of tacrolimus were well controlled at approximately 10&#xa0;ng/mL. Due to the fact that informed consent could not be obtained from this patient, the researchers were unable to access genetic information, and thus it was impossible to determine whether the patient had the CYP2C19 gene mutation (<xref ref-type="bibr" rid="B29">Takahashi et al., 2007</xref>).</p>
<p>In another case report, an increase in tacrolimus concentrations was also observed after the administration of omeprazole. Zhao W. et al. (<xref ref-type="bibr" rid="B34">Zhao WFM. et al., 2012</xref>) found a more than four-fold increase in tacrolimus concentrations after omeprazole administration in a 17-year-old kidney transplant patient. The immunosuppressive regimen in this case comprised tacrolimus, mycophenolate mofetil and methylprednisolone. The initial dose of tacrolimus was 9&#xa0;mg twice daily, which resulted in tacrolimus blood trough levels (C<sub>0</sub>) of 19.6 and 29.2&#xa0;ng/mL postoperatively on days 3 and 4, respectively, and the dose was consequently reduced to 7&#xa0;mg. On postoperative day 5, omeprazole was administered to alleviate gastric reflux. Despite tacrolimus dose reduction, on postoperative day 6, C0 increased to 92&#xa0;ng/mL and induced acute nephrotoxicity (serum creatinine 160&#xa0;mmol/L). Tacrolimus treatment was resumed on postoperative day 7 based on TDM results, whereas omeprazole treatment was discontinued. Subsequently, the nephrotoxicity was reversed (serum creatinine returned to baseline and steadily decreased in the days following surgery). The patient was found to be homozygous for the (&#x2a;2/&#x2a;2) CYP2C19 mutation, which resulted in an abnormal splicing site that significantly reduced or inactivated the activity of the encoded CYP2C19 protein, and thus was classified as a poor CYP2C19 metabolizer (<xref ref-type="bibr" rid="B33">Zhao W. et al., 2012</xref>).</p>
<p>In our study, genetic testing was not conducted, although the patients were evaluated with regard to their drug metabolism rate according to the C/D ratio, as suggested by Th&#xf6;lking G. et al. Patients were classified as intermediate metabolisers with a C/D ratio between 1.05 and 1.54&#xa0;ng/mL&#x2a;1/mg. In turn, if the C/D ratio was &#x3c;1.05&#xa0;ng/mL&#x2a;1/mg, they were described as fast metabolizers, whereas if the said ratio was &#x2265;1.55&#xa0;ng/mL&#x2a;1/mg, the participants were referred to as slow metabolizers (<xref ref-type="bibr" rid="B31">Tholking et al., 2014</xref>). It is of note that the mean C/D ratio was higher in the famotidine group than in the omeprazole group, which emphasise the relevance of our results regarding the significant changes in tacrolimus concentrations observed within the omeprazole group. CYP2C19 is predominantly involved in the metabolism of omeprazole; however, in the case of the CYP2C19 gene mutation (in poor metabolizers), CYP3A4/5 becomes the main enzyme participating in the elimination of omeprazole. In addition, tacrolimus is also metabolized by CYP3A4/5, which may lead to a competition for CYP3A4/5 enzymes whereby the metabolism of tacrolimus may be insufficient. This, in turn, may result in increased the concentrations of tacrolimus, which may affect the process of chronic renal rejection. In contrast, famotidine is not a substrate of CYP3A4/CYP3A5 and, therefore, does not interact with tacrolimus. In their study involving 75 patients, Boso V. et al. demonstrated that recipients with the CYP2C19&#x2a;2/&#x2a;2 genotype presented higher blood concentrations of tacrolimus as compared to those without the mutations during treatment with tacrolimus and omeprazole (<xref ref-type="bibr" rid="B1">Boso et al., 2013</xref>). Nevertheless, it should also be noted that Pascual J. et al. in a case-analytical study (n &#x3d; 51) concluded that the interaction of omeprazole with tacrolimus was of no clinical significance. Despite the potential competition or interaction at the molecular level, the clinical management was not significantly affected in renal allograft recipients. Tacrolimus doses and the level/dose ratio were recorded 7 times: at 3 outpatient appointments prior to omeprazole withdrawal (Pre3/Pre2/Pre1), at the withdrawal appointment (Susp), and at 3 post-withdrawal appointments (Pos1/Pos2/Pos3). The abovementioned appointments were approximately 1 month apart. Pascual et al. observed the slow, progressive decline in tacrolimus concentration throughout the study, and hence concluded that there was no significant drug interaction between omeprazole and tacrolimus (<xref ref-type="bibr" rid="B20">Pascual et al., 2005</xref>). Conversely, according to a double-blind, placebo-controlled pilot study (n &#x3d; 28) by Peloso et al., omeprazole may increase the blood concentration of tacrolimus if administered 2&#xa0;h before receiving tacrolimus, potentially as a result of intestinal contents alkalization (<xref ref-type="bibr" rid="B22">Peloso et al., 2014</xref>). On the basis of the available studies and case reports, it seems reasonable to avoid omeprazole administration in patients receiving tacrolimus, regardless of the CYP2C19 genotype (<xref ref-type="bibr" rid="B12">Maguire et al., 2012</xref>). It is worth bearing in mind that triclopidine, fluvoxamine, voriconazole, fluconazole, ketoconazole and fluoxetine represent potent inhibitors of the CYP2C19 enzyme (<xref ref-type="bibr" rid="B32">Yasui-Furukori et al., 2004</xref>; <xref ref-type="bibr" rid="B11">Jeong et al., 2009</xref>; <xref ref-type="bibr" rid="B8">Harvey and Preskorn, 2001</xref>). Therefore, the use of a CYP2C19 inhibitor in renal transplant patients where omeprazole and tacrolimus are administered may result in drug interactions. The inhibition of the CYP2C19 isoform may suppress the metabolism of omeprazole by means of the CYP2C19 enzyme. Furthermore, in order to maintain adequate biotransformation, omeprazole may alter its metabolic pathway to be metabolized by the CYP3A4 enzyme, which may lead to drug interactions with tacrolimus. In addition, the competition for the CYP3A4 enzyme may affect the metabolism of tacrolimus, resulting in increased the concentrations of tacrolimus, which in turn may trigger adverse reactions and, consequently, lead to the development of chronic dysfunction of the transplanted kidney. It should also be noted that one of the side effects of tacrolimus is nephrotoxicity. In contrast, famotidine does not interact with the drug-metabolizing enzyme system associated with cytochrome P450, and therefore is a good candidate to be administered instead of omeprazole (<xref ref-type="bibr" rid="B10">Itagaki et al., 2002</xref>). In addition to the role of cytochrome P450 described above, the effect of P-glycoprotein (P-gp) is also important in the interaction under study. The increase in tacrolimus exposure observed in our study when coadministered with omeprazole vs. without omeprazole may be a result of intestinal P-gp inhibition by omeprazole (<xref ref-type="bibr" rid="B21">Pauli-Magnus et al., 2001</xref>). During tacrolimus-omeprazole interactions at the level of the ABCB1 transporter, the absorption of tacrolimus increases, which may result in an increase in drug concentration in blood (<xref ref-type="bibr" rid="B34">Zhao WFM. et al., 2012</xref>; <xref ref-type="bibr" rid="B23">Peng et al., 2020</xref>). Additionally, another mechanism related to lipophilicity/binding to plasma proteins of famotidine (low lipophilicity: XlogP3 &#x3d; &#x2212;0.6), omeprazole (high lipophilicity: XLogP3 &#x3d; 2.2), and tacrolimus (high lipophilicity: XLogP3 &#x3d; 2.7) may play a key role (<xref ref-type="bibr" rid="B17">National Center for Biotechnology Information, 2005a</xref>; <xref ref-type="bibr" rid="B18">National Center for Biotechnology Information, 2005b</xref>; <xref ref-type="bibr" rid="B19">National Center for Biotechnology Information, 2005c</xref>). Omerpazole (approximately 95%) and tacrolimus (approximately 99% of) highly bound to plasma proteins. It means that both drugs compete with binding sites. In effect, more tacrolimus molecules are in non-bound (free fraction) in the bloodstream. In consequence, higher AUC was observed.</p>
<p>C<sub>0</sub> is used in most transplant centers for routine therapeutic drug monitoring of tacrolimus (<xref ref-type="bibr" rid="B2">Brunet et al., 2019</xref>). In our study, we observed that the AUC<sub>2-6</sub> value plays a greater role in assessing the occurrence of omeprazole-tacrolimus interactions than the C<sub>0</sub> or C<sub>2</sub> value. AUC<sub>2-6</sub> may be an important pharmacokinetic parameter assessing the occurrence of drug-drug interactions in patients following kidney transplantation taking tacrolimus after a single administration of a specific drug. The results of our study may have clinical significance. This is the first cohort study to evaluate the effect of famotidine on tacrolimus concentrations in patients following kidney transplantation. Famotidine have not effected on the pharmacokinetics of tacrolimus, so it may be an alternative to proton pump inhibitors in the prevention of upper gastrointestinal bleeding in patients after kidney transplantation. Moreover, unlike proton pump inhibitors, famotidine does not have a nephrotoxic effect. Moreover, the observed nephrotoxicity in patients following kidney transplantation may be related to the combined use of omeprazole or the effect of the drug on the concentration of nephrotoxic tacrolimus. A significant limitation of our study is the small group of patients. However, despite such a limited number of subjects, our results were found to be significant. Obtaining statistically significant results considering the number of patients studied highlights the significant difference between the change in tacrolimus concentration after administrating with omeprazole vs. without omeprazole. No such change was observed compared to administrating tacrolimus with famotidine. As a result, after repeated combined administration of both drugs, omeprazole may increase tacrolimus concentrations to toxic levels, which may result in nephrotoxicity of the drug. No such change was observed compared to administration of tacrolimus with famotidine. It is important to investigate the effects of omeprazole and famotidine on tacrolimus concentrations after repeated dosing. Furthermore, the number of tacrolimus concentration measurements in the course of the study (30&#xa0;h) could have been higher. Yet, due to the pain associated with collecting blood samples, it was impossible to determine these concentrations more frequently. It would also be clinically important to conduct a study assessing the long-term effect of the studied drugs on the pharmacokinetics of tacrolimus, as well as assessing the function a transplanted kidney and markers of the rejection process of a transplanted kidney in the study groups over time.</p>
</sec>
<sec sec-type="conclusion" id="s5">
<title>5 Conclusion</title>
<p>Co-administration of omeprazole and tacrolimus in renal transplant patients presents greater difficulties in maintaining tacrolimus concentrations within the therapeutic range than the combination of famotidine and tacrolimus. Moreover, in contrast to famotidine, omeprazole significantly increased blood exposure of tacrolimus. Therefore, the use of famotidine instead of omeprazole seems to be more beneficial and safer for patients following kidney transplantation. Given the results of our study and the widely reported nephrotoxicity of omeprazole, the administration of this medication is not recommended in renal transplant patients.</p>
</sec>
</body>
<back>
<sec sec-type="data-availability" id="s6">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/<xref ref-type="sec" rid="s12">Supplementary Material</xref>, further inquiries can be directed to the corresponding author.</p>
</sec>
<sec id="s7">
<title>Ethics statement</title>
<p>The studies involving humans were approved by The Bioethical Commission at the Poznan University of Medical Sciences (No. 687/20). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.</p>
</sec>
<sec id="s8">
<title>Author contributions</title>
<p>MM: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing&#x2013;original draft. MK: Funding acquisition, Investigation, Resources, Writing&#x2013;review and editing. TG: Methodology, Writing&#x2013;review and editing. AW: Formal Analysis, Writing&#x2013;review and editing. IT-P: Conceptualization, Funding acquisition, Investigation, Resources, Supervision, Writing&#x2013;review and editing.</p>
</sec>
<sec sec-type="funding-information" id="s9">
<title>Funding</title>
<p>The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The study was financed with the academic grant of the Pozna&#x144; University of Medical Sciences (grant No. 502-14-12253630&#x2013;45064).</p>
</sec>
<sec sec-type="COI-statement" id="s10">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec sec-type="disclaimer" id="s11">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<sec id="s12">
<title>Supplementary material</title>
<p>The Supplementary Material for this article can be found online at: <ext-link ext-link-type="uri" xlink:href="https://www.frontiersin.org/articles/10.3389/fphar.2024.1352323/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fphar.2024.1352323/full&#x23;supplementary-material</ext-link>
</p>
<supplementary-material xlink:href="DataSheet2.PDF" id="SM1" mimetype="application/PDF" xmlns:xlink="http://www.w3.org/1999/xlink"/>
<supplementary-material xlink:href="DataSheet1.pdf" id="SM2" mimetype="application/pdf" xmlns:xlink="http://www.w3.org/1999/xlink"/>
</sec>
<ref-list>
<title>References</title>
<ref id="B1">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Boso</surname>
<given-names>V.</given-names>
</name>
<name>
<surname>Herrero</surname>
<given-names>M. J.</given-names>
</name>
<name>
<surname>Bea</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Galiana</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Marrero</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Marques</surname>
<given-names>M. R.</given-names>
</name>
<etal/>
</person-group> (<year>2013</year>). <article-title>Increased hospital stay and allograft dysfunction in renal transplant recipients with Cyp2c19 AA variant in SNP rs4244285</article-title>. <source>Drug Metab. Dispos.</source> <volume>41</volume> (<issue>2</issue>), <fpage>480</fpage>&#x2013;<lpage>487</lpage>. <pub-id pub-id-type="doi">10.1124/dmd.112.047977</pub-id>
</citation>
</ref>
<ref id="B2">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Brunet</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>van Gelder</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Asberg</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Haufroid</surname>
<given-names>V.</given-names>
</name>
<name>
<surname>Hesselink</surname>
<given-names>D. A.</given-names>
</name>
<name>
<surname>Langman</surname>
<given-names>L.</given-names>
</name>
<etal/>
</person-group> (<year>2019</year>). <article-title>Therapeutic drug monitoring of tacrolimus-personalized therapy: second consensus report</article-title>. <source>Ther. Drug Monit.</source> <volume>41</volume> (<issue>3</issue>), <fpage>261</fpage>&#x2013;<lpage>307</lpage>. <pub-id pub-id-type="doi">10.1097/FTD.0000000000000640</pub-id>
</citation>
</ref>
<ref id="B3">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Budde</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Rostaing</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Maggiore</surname>
<given-names>U.</given-names>
</name>
<name>
<surname>Piotti</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Surace</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Geraci</surname>
<given-names>S.</given-names>
</name>
<etal/>
</person-group> (<year>2022</year>). <article-title>Prolonged-release once-daily formulation of tacrolimus versus standard-of-care tacrolimus in <italic>de novo</italic> kidney transplant patients across Europe</article-title>. <source>Transpl. Int.</source> <volume>35</volume>, <fpage>10225</fpage>. <pub-id pub-id-type="doi">10.3389/ti.2021.10225</pub-id>
</citation>
</ref>
<ref id="B4">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Christians</surname>
<given-names>U.</given-names>
</name>
<name>
<surname>Schmidt</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Bader</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Lampen</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Schottmann</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Linck</surname>
<given-names>A.</given-names>
</name>
<etal/>
</person-group> (<year>1996</year>). <article-title>Identification of drugs inhibiting the <italic>in vitro</italic> metabolism of tacrolimus by human liver microsomes</article-title>. <source>Br. J. Clin. Pharmacol.</source> <volume>41</volume> (<issue>3</issue>), <fpage>187</fpage>&#x2013;<lpage>190</lpage>. <pub-id pub-id-type="doi">10.1111/j.1365-2125.1996.tb00181.x</pub-id>
</citation>
</ref>
<ref id="B5">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Dehbozorgi</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Kamalidehghan</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Hosseini</surname>
<given-names>I.</given-names>
</name>
<name>
<surname>Dehghanfard</surname>
<given-names>Z.</given-names>
</name>
<name>
<surname>Sangtarash</surname>
<given-names>M. H.</given-names>
</name>
<name>
<surname>Firoozi</surname>
<given-names>M.</given-names>
</name>
<etal/>
</person-group> (<year>2018</year>). <article-title>Prevalence of the CYP2C19&#x2a;2 (681 G&#x3e;A), &#x2a;3 (636 G&#x3e;A) and &#x2a;17 (-806 C&#x3e;T) alleles among an Iranian population of different ethnicities</article-title>. <source>Mol. Med. Rep.</source> <volume>17</volume> (<issue>3</issue>), <fpage>4195</fpage>&#x2013;<lpage>4202</lpage>. <pub-id pub-id-type="doi">10.3892/mmr.2018.8377</pub-id>
</citation>
</ref>
<ref id="B6">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Floren</surname>
<given-names>L. C.</given-names>
</name>
<name>
<surname>Bekersky</surname>
<given-names>I.</given-names>
</name>
<name>
<surname>Benet</surname>
<given-names>L. Z.</given-names>
</name>
<name>
<surname>Mekki</surname>
<given-names>Q.</given-names>
</name>
<name>
<surname>Dressler</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Lee</surname>
<given-names>J. W.</given-names>
</name>
<etal/>
</person-group> (<year>1997</year>). <article-title>Tacrolimus oral bioavailability doubles with coadministration of ketoconazole</article-title>. <source>Clin. Pharmacol. Ther.</source> <volume>62</volume> (<issue>1</issue>), <fpage>41</fpage>&#x2013;<lpage>49</lpage>. <pub-id pub-id-type="doi">10.1016/S0009-9236(97)90150-8</pub-id>
</citation>
</ref>
<ref id="B7">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Franco</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Mas-Serrano</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Balibrea</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Rodriguez</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Javaloyes</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Diaz</surname>
<given-names>M.</given-names>
</name>
<etal/>
</person-group> (<year>2019</year>). <article-title>Envarsus, a novelty for transplant nephrologists: observational retrospective study</article-title>. <source>Nefrol. Engl. Ed.</source> <volume>39</volume> (<issue>5</issue>), <fpage>506</fpage>&#x2013;<lpage>512</lpage>. <pub-id pub-id-type="doi">10.1016/j.nefro.2018.11.009</pub-id>
</citation>
</ref>
<ref id="B8">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Harvey</surname>
<given-names>A. T.</given-names>
</name>
<name>
<surname>Preskorn</surname>
<given-names>S. H.</given-names>
</name>
</person-group> (<year>2001</year>). <article-title>Fluoxetine pharmacokinetics and effect on CYP2C19 in young and elderly volunteers</article-title>. <source>J. Clin. Psychopharmacol.</source> <volume>21</volume> (<issue>2</issue>), <fpage>161</fpage>&#x2013;<lpage>166</lpage>. <pub-id pub-id-type="doi">10.1097/00004714-200104000-00007</pub-id>
</citation>
</ref>
<ref id="B9">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hosohata</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Masuda</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Katsura</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Takada</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Kaido</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Ogura</surname>
<given-names>Y.</given-names>
</name>
<etal/>
</person-group> (<year>2009</year>). <article-title>Impact of intestinal CYP2C19 genotypes on the interaction between tacrolimus and omeprazole, but not lansoprazole, in adult living-donor liver transplant patients</article-title>. <source>Drug Metab. Dispos.</source> <volume>37</volume> (<issue>4</issue>), <fpage>821</fpage>&#x2013;<lpage>826</lpage>. <pub-id pub-id-type="doi">10.1124/dmd.108.025833</pub-id>
</citation>
</ref>
<ref id="B10">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Itagaki</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Homma</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Yuzawa</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Fukao</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Kohda</surname>
<given-names>Y.</given-names>
</name>
</person-group> (<year>2002</year>). <article-title>Drug interaction of tacrolimus and proton pump inhibitors in renal transplant recipients with CYP2C19 gene mutation</article-title>. <source>Transpl. Proc.</source> <volume>34</volume> (<issue>7</issue>), <fpage>2777</fpage>&#x2013;<lpage>2778</lpage>. <pub-id pub-id-type="doi">10.1016/s0041-1345(02)03409-7</pub-id>
</citation>
</ref>
<ref id="B11">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Jeong</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Nguyen</surname>
<given-names>P. D.</given-names>
</name>
<name>
<surname>Desta</surname>
<given-names>Z.</given-names>
</name>
</person-group> (<year>2009</year>). <article-title>Comprehensive <italic>in vitro</italic> analysis of voriconazole inhibition of eight cytochrome P450 (CYP) enzymes: major effect on CYPs 2B6, 2C9, 2C19, and 3A</article-title>. <source>Antimicrob. Agents Chemother.</source> <volume>53</volume> (<issue>2</issue>), <fpage>541</fpage>&#x2013;<lpage>551</lpage>. <pub-id pub-id-type="doi">10.1128/AAC.01123-08</pub-id>
</citation>
</ref>
<ref id="B12">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Maguire</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Franz</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Hains</surname>
<given-names>D. S.</given-names>
</name>
</person-group> (<year>2012</year>). <article-title>A clinically significant interaction between tacrolimus and multiple proton pump inhibitors in a kidney transplant recipient</article-title>. <source>Pediatr. Transpl.</source> <volume>16</volume> (<issue>6</issue>), <fpage>E217</fpage>&#x2013;<lpage>E220</lpage>. <pub-id pub-id-type="doi">10.1111/j.1399-3046.2011.01559.x</pub-id>
</citation>
</ref>
<ref id="B13">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Marfo</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Altshuler</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Lu</surname>
<given-names>A.</given-names>
</name>
</person-group> (<year>2010</year>). <article-title>Tacrolimus pharmacokinetic and pharmacogenomic differences between adults and pediatric solid organ transplant recipients</article-title>. <source>Pharmaceutics</source> <volume>2</volume> (<issue>3</issue>), <fpage>291</fpage>&#x2013;<lpage>299</lpage>. <pub-id pub-id-type="doi">10.3390/pharmaceutics2030291</pub-id>
</citation>
</ref>
<ref id="B14">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Mei</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Chen</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Zhu</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Zhao</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Tian</surname>
<given-names>X.</given-names>
</name>
<etal/>
</person-group> (<year>2018</year>). <article-title>Simultaneous determination of cyclosporine and tacrolimus in human whole blood by ultra-high performance liquid chromatography tandem mass spectrometry and comparison with a chemiluminescence microparticle immunoassay</article-title>. <source>J. Chromatogr. B Anal. Technol. Biomed. Life Sci.</source> <volume>1087</volume>, <fpage>36</fpage>&#x2013;<lpage>42</lpage>. <pub-id pub-id-type="doi">10.1016/j.jchromb.2018.04.028</pub-id>
</citation>
</ref>
<ref id="B15">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Miedziaszczyk</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Idasiak-Piechocka</surname>
<given-names>I.</given-names>
</name>
</person-group> (<year>2023</year>). <article-title>Safety analysis of co-administering tacrolimus and omeprazole in renal transplant recipients - a review</article-title>. <source>Biomed. Pharmacother.</source> <volume>166</volume>, <fpage>115149</fpage>. <pub-id pub-id-type="doi">10.1016/j.biopha.2023.115149</pub-id>
</citation>
</ref>
<ref id="B16">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Moreau</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Debray</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Loriot</surname>
<given-names>M. A.</given-names>
</name>
<name>
<surname>Taburet</surname>
<given-names>A. M.</given-names>
</name>
<name>
<surname>Furlan</surname>
<given-names>V.</given-names>
</name>
</person-group> (<year>2006</year>). <article-title>Interaction between tacrolimus and omeprazole in a pediatric liver transplant recipient</article-title>. <source>Transplantation</source> <volume>81</volume> (<issue>3</issue>), <fpage>487</fpage>&#x2013;<lpage>488</lpage>. <pub-id pub-id-type="doi">10.1097/01.tp.0000194861.59543.b9</pub-id>
</citation>
</ref>
<ref id="B17">
<citation citation-type="web">
<collab>National Center for Biotechnology Information</collab> <article-title>PubChem compound summary for CID 445643, tacrolimus</article-title>.<year>2005</year> <comment>Access: <ext-link ext-link-type="uri" xlink:href="https://pubchem.ncbi.nlm.nih.gov/compound/Tacrolimus">https://pubchem.ncbi.nlm.nih.gov/compound/Tacrolimus</ext-link>
</comment>.</citation>
</ref>
<ref id="B18">
<citation citation-type="web">
<collab>National Center for Biotechnology Information</collab> <year>2005</year> <article-title>PubChem compound summary for CID 4594, omeprazole</article-title>. <comment>Access: <ext-link ext-link-type="uri" xlink:href="https://pubchem.ncbi.nlm.nih.gov/compound/Omeprazole">https://pubchem.ncbi.nlm.nih.gov/compound/Omeprazole</ext-link>
</comment>.</citation>
</ref>
<ref id="B19">
<citation citation-type="web">
<collab>National Center for Biotechnology Information</collab> <article-title>PubChem compound summary for CID 5702160, famotidine</article-title>. <year>2005</year> <comment>Access: <ext-link ext-link-type="uri" xlink:href="https://pubchem.ncbi.nlm.nih.gov/compound/Amfamox">https://pubchem.ncbi.nlm.nih.gov/compound/Amfamox</ext-link>
</comment>.</citation>
</ref>
<ref id="B20">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Pascual</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Marcen</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Orea</surname>
<given-names>O. E.</given-names>
</name>
<name>
<surname>Navarro</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Alarcon</surname>
<given-names>M. C.</given-names>
</name>
<name>
<surname>Ocana</surname>
<given-names>J.</given-names>
</name>
<etal/>
</person-group> (<year>2005</year>). <article-title>Interaction between omeprazole and tacrolimus in renal allograft recipients: a clinical-analytical study</article-title>. <source>Transpl. Proc.</source> <volume>37</volume> (<issue>9</issue>), <fpage>3752</fpage>&#x2013;<lpage>3753</lpage>. <pub-id pub-id-type="doi">10.1016/j.transproceed.2005.09.126</pub-id>
</citation>
</ref>
<ref id="B21">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Pauli-Magnus</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Rekersbrink</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Klotz</surname>
<given-names>U.</given-names>
</name>
<name>
<surname>Fromm</surname>
<given-names>M. F.</given-names>
</name>
</person-group> (<year>2001</year>). <article-title>Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein</article-title>. <source>Naunyn Schmiedeb. Arch. Pharmacol.</source> <volume>364</volume> (<issue>6</issue>), <fpage>551</fpage>&#x2013;<lpage>557</lpage>. <pub-id pub-id-type="doi">10.1007/s00210-001-0489-7</pub-id>
</citation>
</ref>
<ref id="B22">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Peloso</surname>
<given-names>L. J.</given-names>
</name>
<name>
<surname>Faria</surname>
<given-names>P. N.</given-names>
</name>
<name>
<surname>Bossolani</surname>
<given-names>M. V.</given-names>
</name>
<name>
<surname>de Oliveira</surname>
<given-names>H. B.</given-names>
</name>
<name>
<surname>Ferreira Filho</surname>
<given-names>S. R.</given-names>
</name>
</person-group> (<year>2014</year>). <article-title>The serum concentration of tacrolimus after ingesting omeprazole: a pilot study</article-title>. <source>Transplantation</source> <volume>98</volume> (<issue>6</issue>), <fpage>e63</fpage>&#x2013;<lpage>e64</lpage>. <pub-id pub-id-type="doi">10.1097/TP.0000000000000351</pub-id>
</citation>
</ref>
<ref id="B23">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Peng</surname>
<given-names>W.</given-names>
</name>
<name>
<surname>Lin</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Meng</surname>
<given-names>K.</given-names>
</name>
</person-group> (<year>2020</year>). <article-title>Effect of ABCB1 3435C&#x3e;T genetic polymorphism on pharmacokinetic variables of tacrolimus in adult renal transplant recipients: a systematic review and meta-analysis</article-title>. <source>Clin. Ther.</source> <volume>42</volume> (<issue>10</issue>), <fpage>2049</fpage>&#x2013;<lpage>2065</lpage>. <pub-id pub-id-type="doi">10.1016/j.clinthera.2020.07.016</pub-id>
</citation>
</ref>
<ref id="B24">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ponticelli</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Passerini</surname>
<given-names>P.</given-names>
</name>
</person-group> (<year>2005</year>). <article-title>Gastrointestinal complications in renal transplant recipients</article-title>. <source>Transpl. Int.</source> <volume>18</volume> (<issue>6</issue>), <fpage>643</fpage>&#x2013;<lpage>650</lpage>. <pub-id pub-id-type="doi">10.1111/j.1432-2277.2005.00134.x</pub-id>
</citation>
</ref>
<ref id="B25">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Sugimoto</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Furuta</surname>
<given-names>T.</given-names>
</name>
</person-group> (<year>2012</year>). <article-title>Efficacy of esomeprazole in treating acid-related diseases in Japanese populations</article-title>. <source>Clin. Exp. Gastroenterol.</source> <volume>5</volume>, <fpage>49</fpage>&#x2013;<lpage>59</lpage>. <pub-id pub-id-type="doi">10.2147/CEG.S23926</pub-id>
</citation>
</ref>
<ref id="B26">
<citation citation-type="web">
<article-title>Summary of product characteristics of omeprazole</article-title> <comment>Access: <ext-link ext-link-type="uri" xlink:href="https://www.medicines.org.uk/emc/product/4895/smpc#gref">https://www.medicines.org.uk/emc/product/4895/smpc&#x23;gref</ext-link>
</comment>].</citation>
</ref>
<ref id="B27">
<citation citation-type="web">
<article-title>Summary of product characteristics of tacrolimus</article-title> <comment>Access: <ext-link ext-link-type="uri" xlink:href="https://www.medicines.org.uk/emc/product/7804/smpc">https://www.medicines.org.uk/emc/product/7804/smpc</ext-link>
</comment>] (<comment>Accessed March 6, 2024</comment>).</citation>
</ref>
<ref id="B28">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Susal</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Dohler</surname>
<given-names>B.</given-names>
</name>
</person-group> (<year>2019</year>). <article-title>Late intra-patient tacrolimus trough level variability as a major problem in kidney transplantation: a Collaborative Transplant Study Report</article-title>. <source>Am. J. Transpl.</source> <volume>19</volume> (<issue>10</issue>), <fpage>2805</fpage>&#x2013;<lpage>2813</lpage>. <pub-id pub-id-type="doi">10.1111/ajt.15346</pub-id>
</citation>
</ref>
<ref id="B29">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Takahashi</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Yano</surname>
<given-names>I.</given-names>
</name>
<name>
<surname>Fukuhara</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Katsura</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Takahashi</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Ito</surname>
<given-names>N.</given-names>
</name>
<etal/>
</person-group> (<year>2007</year>). <article-title>Distinct effects of omeprazole and rabeprazole on the tacrolimus blood concentration in a kidney transplant recipient</article-title>. <source>Drug Metab. Pharmacokinet.</source> <volume>22</volume> (<issue>6</issue>), <fpage>441</fpage>&#x2013;<lpage>444</lpage>. <pub-id pub-id-type="doi">10.2133/dmpk.22.441</pub-id>
</citation>
</ref>
<ref id="B30">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Telkes</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Peter</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Tulassay</surname>
<given-names>Z.</given-names>
</name>
<name>
<surname>Asderakis</surname>
<given-names>A.</given-names>
</name>
</person-group> (<year>2011</year>). <article-title>High frequency of ulcers, not associated with <italic>Helicobacter pylori</italic>, in the stomach in the first year after kidney transplantation</article-title>. <source>Nephrol. Dial. Transpl.</source> <volume>26</volume> (<issue>2</issue>), <fpage>727</fpage>&#x2013;<lpage>732</lpage>. <pub-id pub-id-type="doi">10.1093/ndt/gfq401</pub-id>
</citation>
</ref>
<ref id="B31">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Tholking</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Fortmann</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Koch</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Gerth</surname>
<given-names>H. U.</given-names>
</name>
<name>
<surname>Pabst</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Pavenstadt</surname>
<given-names>H.</given-names>
</name>
<etal/>
</person-group> (<year>2014</year>). <article-title>The tacrolimus metabolism rate influences renal function after kidney transplantation</article-title>. <source>PLoS One</source> <volume>9</volume> (<issue>10</issue>), <fpage>e111128</fpage>. <pub-id pub-id-type="doi">10.1371/journal.pone.0111128</pub-id>
</citation>
</ref>
<ref id="B32">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Yasui-Furukori</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Takahata</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Nakagami</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Yoshiya</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Inoue</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Kaneko</surname>
<given-names>S.</given-names>
</name>
<etal/>
</person-group> (<year>2004</year>). <article-title>Different inhibitory effect of fluvoxamine on omeprazole metabolism between CYP2C19 genotypes</article-title>. <source>Br. J. Clin. Pharmacol.</source> <volume>57</volume> (<issue>4</issue>), <fpage>487</fpage>&#x2013;<lpage>494</lpage>. <pub-id pub-id-type="doi">10.1111/j.1365-2125.2003.02047.x</pub-id>
</citation>
</ref>
<ref id="B33">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Zhao</surname>
<given-names>W.</given-names>
</name>
<name>
<surname>Fakhoury</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Maisin</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Baudouin</surname>
<given-names>V.</given-names>
</name>
<name>
<surname>Storme</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Deschenes</surname>
<given-names>G.</given-names>
</name>
<etal/>
</person-group> (<year>2012b</year>). <article-title>Pharmacogenetic determinant of the drug interaction between tacrolimus and omeprazole</article-title>. <source>Ther. Drug Monit.</source> <volume>34</volume> (<issue>6</issue>), <fpage>739</fpage>&#x2013;<lpage>741</lpage>. <pub-id pub-id-type="doi">10.1097/FTD.0b013e318271b6e6</pub-id>
</citation>
</ref>
<ref id="B34">
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Zhao</surname>
<given-names>W. F. M.</given-names>
</name>
<name>
<surname>Maisin</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Baudouin</surname>
<given-names>V.</given-names>
</name>
<name>
<surname>Storme</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Deschenes</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Jacqz-Aigrain</surname>
<given-names>E.</given-names>
</name>
<etal/>
</person-group> (<year>2012a</year>). <article-title>Pharmacogenetic determinant of the drug interaction between tacrolimus and omeprazole</article-title>. <source>Ther. Drug Monit.</source> <volume>34</volume> (<issue>6</issue>), <fpage>739</fpage>&#x2013;<lpage>741</lpage>. <pub-id pub-id-type="doi">10.1097/FTD.0b013e318271b6e6</pub-id>
</citation>
</ref>
</ref-list>
</back>
</article>