{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T04:09:57Z","timestamp":1748923797948,"version":"3.41.0"},"reference-count":48,"publisher":"Georg Thieme Verlag KG","issue":"05","funder":[{"name":"Pamukkale University Scientific Research\n                    Coordination Unit","award":["2020FEBE029"],"award-info":[{"award-number":["2020FEBE029"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Drug Res (Stuttg)"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mesalamine (mesalazine, 5-aminosalicylic acid, 5-ASA) is an essential\n                    anti-inflammatory agent both used for therapy and as a remission control in\n                    patients with inflammatory bowel diseases (IBD) such as ulcerative colitis (UC).\n                    Tricyclic antidepressants (TCAs) are used to alleviate remaining symptoms in\n                    patients already receiving IBD therapy or with quiescent inflammation. The\n                    cytochrome P4502D6 enzyme is involved in the metabolism of TCAs. Hence, it is\n                    crucial to investigate the role of CYP2D6 in 5-ASA metabolism. Initially, in\n                    silico analysis involving the docking of 5-ASA to CYP2D6 and molecular dynamics\n                    simulations was conducted. Next, the rate of O-demethylation of a nonfluorescent\n                    probe 3-[2-(N,N-diethyl-N-methylammonium)-ethyl]-7-methoxy-4-methylcoumarin\n                    (AMMC) into a fluorescent metabolite AMHC\n                    (3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-hydroxy-4-methylcoumarin) was\n                    optimized with baculosomes co-expressing human CYP2D6 and human P450\n                    oxidoreductase (hCPR) to monitor CYP2D6 activity in a microtiter plate assay.\n                    The apparent Km and Vmax were found to be 1.30 \u03bcM and 32.68 pmol\/min\/mg of\n                    protein for the O-demethylation of AMMC to AMHC, and the reaction was linear for\n                    40\u2009min. Then, nonselective inhibition of CYP2D6 activity with various\n                    concentrations of 5-ASA was detected. Finally, the conversion of AMMC to\n                    metabolites was analyzed by HPLC-ESI-MS\/MS spectrometry, and none were\n                    identified. Thus, this study suggests that concurrent use of mesalamine with TCA\n                    may lead to adverse effects, and CYP2D6 genotyping should be routinely performed\n                    on these patients to eliminate possible threats.<\/jats:p>","DOI":"10.1055\/a-2551-2418","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T00:00:26Z","timestamp":1743552026000},"page":"169-178","source":"Crossref","is-referenced-by-count":0,"title":["Possible Drug-Drug Interactions Between Mesalamine and Tricyclic\n                    Antidepressants Through CYP2D6 Metabolism \u2013 In silico and In vitro\n                    Analyses"],"prefix":"10.1055","volume":"75","author":[{"given":"Melek B.","family":"Ozen","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Sciences, Pamukkale University,\n                    Denizli, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isil","family":"Gazioglu","sequence":"additional","affiliation":[{"name":"Department of Food Science and Human Nutrition, Institute of Food and\n                    Agricultural Sciences, Food and Environmental Toxicology Laboratory, University\n                    of Florida, Gainesville, FL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ozden","family":"Ozgun Acar","sequence":"additional","affiliation":[{"name":"Vocational School of Health Services, Pamukkale University, Denizli,\n                    Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huseyin","family":"Guner","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Life and\n                    Natural Sciences, University of Abdullah Gul, Kayseri, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gurkan","family":"Semiz","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Sciences, Pamukkale University,\n                    Denizli, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alaattin","family":"Sen","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Life and\n                    Natural Sciences, University of Abdullah Gul, Kayseri, Turkey"},{"name":"Department of Biology, Faculty of Sciences, Pamukkale University,\n                    Denizli, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2025,4,1]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1056\/NEJMra020831","article-title":"Inflammatory bowel disease","volume":"347","author":"D K Podolsky","year":"2002","journal-title":"N Engl J Med"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"765474","DOI":"10.3389\/fmed.2021.765474","article-title":"Treatment of Inflammatory Bowel Disease: A Comprehensive Review","volume":"8","author":"Z Cai","year":"2021","journal-title":"Front Med (Lausanne)"},{"key":"ref3","first-page":"129","article-title":"A Review on Inflammatory Bowel Diseases: Recent Molecular Pathophysiology\n                    Advances","volume":"16","author":"M Abdulla","year":"2022","journal-title":"Biologics"},{"key":"ref4","first-page":"392","article-title":"5-Aminosalicylic acid","volume":"75","author":"T Lida","year":"2017","journal-title":"Nihon Rinsho"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1080\/14712598.2019.1666101","article-title":"Modern use of 5-aminosalicylic acid compounds for ulcerative colitis","volume":"20","author":"C Le Berre","year":"2020","journal-title":"Expert Opin Biol Ther"},{"key":"ref6","first-page":"CD000543","article-title":"Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis","volume":"8","author":"A Murray","year":"2020","journal-title":"Cochrane Database Syst Rev"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1055\/s-0031-1299685","article-title":"The pharmacological profile and clinical use of mesalazine (5-aminosalicylic\n                    acid)","volume":"62","author":"U Klotz","year":"2012","journal-title":"Arzneimittelforschung"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1155\/S0962935192000243","article-title":"Mechanism of action of 5-arninosalicylic acid","volume":"1","author":"N A Punchard","year":"1992","journal-title":"Mediators Inflamm"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jcmgh.2017.03.010","article-title":"Induction of Colonic Regulatory T Cells by Mesalamine by Activating the Aryl\n                    Hydrocarbon Receptor","volume":"4","author":"K Oh-Oka","year":"2017","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/S2468-1253(21)00014-5","article-title":"Prevalence of symptoms of anxiety and depression in patients with inflammatory\n                    bowel disease: a systematic review and meta-analysis","volume":"6","author":"B Barberio","year":"2021","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"714057","DOI":"10.3389\/fpsyt.2021.714057","article-title":"Depression and Anxiety Disorders in Patients With Inflammatory Bowel\n                    Disease","volume":"12","author":"S Hu","year":"2021","journal-title":"Front Psychiatry"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1093\/ibd\/izaa030","article-title":"Mental Health Costs of Inflammatory Bowel Diseases","volume":"27","author":"E Szigethy","year":"2021","journal-title":"Inflamm Bowel Dis"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"e056982","DOI":"10.1136\/bmjopen-2021-056982","article-title":"Psychological interventions for inflammatory bowel disease: a systematic review\n                    and component network meta-analysis protocol","volume":"12","author":"N Tiles-Sar","year":"2022","journal-title":"BMJ Open"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/S2468-1253(19)30089-5","article-title":"The influence of the brain-gut axis in inflammatory bowel disease and possible\n                    implications for treatment","volume":"4","author":"D J Gracie","year":"2019","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.jpsychores.2017.07.001","article-title":"Prevalence and effectiveness of psychiatric treatments for patients with IBD: A\n                    systematic literature review","volume":"101","author":"I Tarricone","year":"2017","journal-title":"J Psychosom Res"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1097\/MCG.0000000000000049","article-title":"Tricyclic antidepressants for management of residual symptoms in inflammatory\n                    bowel disease","volume":"48","author":"H N Iskandar","year":"2014","journal-title":"J Clin Gastroenterol"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0002-9343(00)00384-3","article-title":"Treatment of functional gastrointestinal disorders with antidepressant\n                    medications: a meta-analysis","volume":"108","author":"J L Jackson","year":"2000","journal-title":"Am J Med"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.3748\/wjg.15.1548","article-title":"Efficacy of tricyclic antidepressants in irritable bowel syndrome: a\n                    meta-analysis","volume":"15","author":"R Rahimi","year":"2009","journal-title":"World J Gastroenterol"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1016\/S0140-6736(02)11203-7","article-title":"Clinical importance of the cytochromes P450","volume":"360","author":"D W Nebert","year":"2002","journal-title":"Lancet"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1080\/03602530903118729","article-title":"New insights into the structural characteristics and functional relevance of the\n                    human cytochrome P450 2D6 enzyme","volume":"41","author":"B Wang","year":"2009","journal-title":"Drug Metab Rev"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ejphar.2013.12.025","article-title":"The endogenous substrates of brain CYP2D","volume":"724","author":"X Wang","year":"2014","journal-title":"Eur J Pharmacol"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1097\/FPC.0b013e32832e0e97","article-title":"Cytochrome P450 2D6","volume":"19","author":"R P Owen","year":"2009","journal-title":"Pharmacogenet Genomics"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nrgastro.2012.2","article-title":"The role of pharmacogenetics in nonmalignant gastrointestinal diseases","volume":"9","author":"M Camilleri","year":"2012","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/cts.12692","article-title":"Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus\n                    Recommendations from the Clinical Pharmacogenetics Implementation Consortium and\n                    Dutch Pharmacogenetics Working Group","volume":"13","author":"K E Caudle","year":"2020","journal-title":"Clin Transl Sci"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/j.pharmthera.2007.09.004","article-title":"Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic,\n                    pharmacoepigenetic and clinical aspects","volume":"116","author":"M Ingelman-Sundberg","year":"2007","journal-title":"Pharmacol Ther"},{"key":"ref26","first-page":"753","article-title":"Characterization of Human CYP450 Isozymes Responsible for the In Vitro Oxidative\n                    Metabolism of Mesalamine Used for Colitis. J Innov","volume":"7","author":"E Kale","year":"2019","journal-title":"Sci Educ"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"H M Berman","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"e1005659","DOI":"10.1371\/journal.pcbi.1005659","article-title":"OpenMM 7: Rapid development of high performance algorithms for molecular\n                    dynamics","volume":"13","author":"P Eastman","year":"2017","journal-title":"PLoS Comput Biol"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/1471-2105-10-168","article-title":"Fpocket: an open source platform for ligand pocket detection","volume":"10","author":"V Le Guilloux","year":"2009","journal-title":"BMC Bioinformatics"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring\n                    function, efficient optimization, and multithreading","volume":"31","author":"O Trott","year":"2010","journal-title":"J Comput Chem"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","article-title":"AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python\n                    Bindings","volume":"61","author":"J Eberhardt","year":"2021","journal-title":"J Chem Inf Model"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: fast, flexible, and free","volume":"26","author":"D Van Der Spoel","year":"2005","journal-title":"J Comput Chem"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1021\/ci500020m","article-title":"Open Source Drug Discovery C, Lynn A. g_mmpbsa--a GROMACS tool for\n                    high-throughput MM-PBSA calculations","volume":"54","author":"R Kumari","year":"2014","journal-title":"J Chem Inf Model"},{"key":"ref38","first-page":"1196","article-title":"The use of 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin\n                    (AMMC) as a specific CYP2D6 probe in human liver microsomes","volume":"29","author":"N Chauret","year":"2001","journal-title":"Drug Metab Dispos"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"3523","DOI":"10.1042\/BCJ20170543","article-title":"Toward a systems approach to the human cytochrome P450 ensemble: interactions\n                    between CYP2D6 and CYP2E1 and their functional consequences","volume":"474","author":"D R Davydov","year":"2017","journal-title":"Biochem J"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.jchromb.2010.12.034","article-title":"Determination of sulphasalazine and its main metabolite sulphapyridine and\n                    5-aminosalicylic acid in human plasma by liquid chromatography\/tandem mass\n                    spectrometry and its application to a pharmacokinetic study","volume":"879","author":"G Z Gu","year":"2011","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1007\/BF02944345","article-title":"Systemic levels of free 5-aminosalicylic acid depend on the nature of the\n                    5-aminosalicyclic acid derivative and not on disease activity or extent in\n                    patients with inflammatory bowel disease","volume":"168","author":"N Mahmud","year":"1999","journal-title":"Ir J Med Sci"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1586\/ecp.12.2","article-title":"Mesalamine in the treatment and maintenance of remission of ulcerative\n                    colitis","volume":"5","author":"M Ham","year":"2012","journal-title":"Expert Rev Clin Pharmacol"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1124\/dmd.30.7.845","article-title":"Cytochrome P450 fluorometric substrates: identification of isoform-selective\n                    probes for rat CYP2D2 and human CYP3A4","volume":"30","author":"D M Stresser","year":"2002","journal-title":"Drug Metab Dispos"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/clpt.1993.43","article-title":"Inhibition by fluoxetine of cytochrome P450 2D6 activity","volume":"53","author":"S V Otton","year":"1993","journal-title":"Clin Pharmacol Ther"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.nantod.2018.02.011","article-title":"Colloidal aggregation: from screening nuisance to formulation nuance","volume":"19","author":"A N Ganesh","year":"2018","journal-title":"Nano Today"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"304","DOI":"10.3390\/chemosensors10080304","article-title":"Recent Advances in Molecular Fluorescent Probes for CYP450 Sensing and\n                    Imaging","volume":"10","author":"H Li","year":"2022","journal-title":"Chemosensors"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"109959","DOI":"10.1016\/j.dyepig.2021.109959","article-title":"A hemicyanine-based fluorescence probe for selective detection of CYP2D6 in\n                    living cells and tumor-bearing mice","volume":"198","author":"S Xu","year":"2022","journal-title":"Dyes and Pigments"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/00008571-199602000-00002","article-title":"P450 superfamily: update on new sequences, gene mapping, accession numbers and\n                    nomenclature","volume":"6","author":"D R Nelson","year":"1996","journal-title":"Pharmacogenetics"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/j.1365-2710.2009.01102.x","article-title":"Relationship of CYP2D6 genetic polymorphisms and the pharmacokinetics of\n                    tramadol in Chinese volunteers","volume":"35","author":"Q Li","year":"2010","journal-title":"J Clin Pharm Ther"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1136\/gut.51.4.548","article-title":"Which 5-ASA?","volume":"51","author":"S P Travis","year":"2002","journal-title":"Gut"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.jchromb.2008.07.026","article-title":"Development and validation of a HPLC-ESI-MS\/MS method for the determination of\n                    5-aminosalicylic acid and its major metabolite N-acetyl-5-aminosalicylic acid in\n                    human plasma","volume":"872","author":"E Pastorini","year":"2008","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.chroma.2006.01.058","article-title":"High-performance liquid-chromatographic determination of 5-aminosalicylic acid\n                    and its metabolites in blood plasma","volume":"1119","author":"M Nobilis","year":"2006","journal-title":"J Chromatogr A"}],"container-title":["Drug Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2551-2418.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T23:05:56Z","timestamp":1748905556000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2551-2418"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,1]]},"references-count":48,"journal-issue":{"issue":"05","published-online":{"date-parts":[[2025,6,2]]},"published-print":{"date-parts":[[2025,6]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2551-2418","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["2194-9379","2194-9387"],"issn-type":[{"type":"print","value":"2194-9379"},{"type":"electronic","value":"2194-9387"}],"subject":[],"published":{"date-parts":[[2025,4,1]]}}}