Possible Drug-Drug Interactions Between Mesalamine and Tricyclic
                    Antidepressants Through CYP2D6 Metabolism – In silico and In vitro
                    Analyses

Melek B. Ozen; Isil Gazioglu; Ozden Ozgun Acar; Huseyin Guner; Gurkan Semiz; Alaattin Sen

doi:10.1055/a-2551-2418

Drug Research, Table of Contents

Drug Res (Stuttg)
DOI: 10.1055/a-2551-2418

Original Article

Possible Drug-Drug Interactions Between Mesalamine and Tricyclic Antidepressants Through CYP2D6 Metabolism – In silico and In vitro Analyses

Melek B. Ozen

¹Department of Biology, Faculty of Sciences, Pamukkale University, Denizli, Turkey

,

Isil Gazioglu

²Department of Food Science and Human Nutrition, Institute of Food and Agricultural Sciences, Food and Environmental Toxicology Laboratory, University of Florida, Gainesville, FL, USA

,

Ozden Ozgun Acar

³Vocational School of Health Services, Pamukkale University, Denizli, Turkey

,

Huseyin Guner

⁴Department of Molecular Biology and Genetics, Faculty of Life and Natural Sciences, University of Abdullah Gul, Kayseri, Turkey

,

Gurkan Semiz

⁵Department of Biology, Faculty of Sciences, Pamukkale University, Denizli, Turkey

,

Alaattin Sen

⁴Department of Molecular Biology and Genetics, Faculty of Life and Natural Sciences, University of Abdullah Gul, Kayseri, Turkey

⁶Department of Biology, Faculty of Sciences, Pamukkale University, Denizli, Turkey

› Author Affiliations

Abstract

Mesalamine (mesalazine, 5-aminosalicylic acid, 5-ASA) is an essential anti-inflammatory agent both used for therapy and as a remission control in patients with inflammatory bowel diseases (IBD) such as ulcerative colitis (UC). Tricyclic antidepressants (TCAs) are used to alleviate remaining symptoms in patients already receiving IBD therapy or with quiescent inflammation. The cytochrome P4502D6 enzyme is involved in the metabolism of TCAs. Hence, it is crucial to investigate the role of CYP2D6 in 5-ASA metabolism. Initially, in silico analysis involving the docking of 5-ASA to CYP2D6 and molecular dynamics simulations was conducted. Next, the rate of O-demethylation of a nonfluorescent probe 3-[2-(N,N-diethyl-N-methylammonium)-ethyl]-7-methoxy-4-methylcoumarin (AMMC) into a fluorescent metabolite AMHC (3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-hydroxy-4-methylcoumarin) was optimized with baculosomes co-expressing human CYP2D6 and human P450 oxidoreductase (hCPR) to monitor CYP2D6 activity in a microtiter plate assay. The apparent Km and Vmax were found to be 1.30 μM and 32.68 pmol/min/mg of protein for the O-demethylation of AMMC to AMHC, and the reaction was linear for 40 min. Then, nonselective inhibition of CYP2D6 activity with various concentrations of 5-ASA was detected. Finally, the conversion of AMMC to metabolites was analyzed by HPLC-ESI-MS/MS spectrometry, and none were identified. Thus, this study suggests that concurrent use of mesalamine with TCA may lead to adverse effects, and CYP2D6 genotyping should be routinely performed on these patients to eliminate possible threats.

Keywords

adverse drug reactions - antipsychotic drugs - drug metabolism - pharmacokinetics

Full Text

References

References
1 Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002; 347: 417-429
2 Cai Z, Wang S, Li J. Treatment of Inflammatory Bowel Disease: A Comprehensive Review. Front Med (Lausanne) 2021; 8: 765474
3 Abdulla M, Mohammed N. A Review on Inflammatory Bowel Diseases: Recent Molecular Pathophysiology Advances. Biologics 2022; 16: 129-140
4 Lida T, Onodera K, Nakase H. 5-Aminosalicylic acid. Nihon Rinsho 2017; 75: 392-397
5 Le Berre C, Roda G, Nedeljkovic Protic M. et al. Modern use of 5-aminosalicylic acid compounds for ulcerative colitis. Expert Opin Biol Ther 2020; 20: 363-378
6 Murray A, Nguyen TM, Parker CE. et al. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2020; 8: CD000543
7 Klotz U. The pharmacological profile and clinical use of mesalazine (5-aminosalicylic acid). Arzneimittelforschung 2012; 62: 53-58
8 Punchard NA, Greenfield SM, Thompson RP. Mechanism of action of 5-arninosalicylic acid. Mediators Inflamm 1992; 1: 151-165
9 Oh-Oka K, Kojima Y, Uchida K. et al. Induction of Colonic Regulatory T Cells by Mesalamine by Activating the Aryl Hydrocarbon Receptor. Cell Mol Gastroenterol Hepatol 2017; 4: 135-151
10 Barberio B, Zamani M, Black CJ. et al. Prevalence of symptoms of anxiety and depression in patients with inflammatory bowel disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2021; 6: 359-370
11 Hu S, Chen Y, Chen Y. et al. Depression and Anxiety Disorders in Patients With Inflammatory Bowel Disease. Front Psychiatry 2021; 12: 714057
12 Szigethy E, Murphy SM, Ehrlich OG. et al. Mental Health Costs of Inflammatory Bowel Diseases. Inflamm Bowel Dis 2021; 27: 40-48
13 Tiles-Sar N, Neuser J, de Sordi D. et al. Psychological interventions for inflammatory bowel disease: a systematic review and component network meta-analysis protocol. BMJ Open 2022; 12: e056982
14 Gracie DJ, Hamlin PJ, Ford AC. The influence of the brain-gut axis in inflammatory bowel disease and possible implications for treatment. Lancet Gastroenterol Hepatol 2019; 4: 632-642
15 Tarricone I, Regazzi MG, Bonucci G. et al. Prevalence and effectiveness of psychiatric treatments for patients with IBD: A systematic literature review. J Psychosom Res 2017; 101: 68-95
16 Iskandar HN, Cassell B, Kanuri N. et al. Tricyclic antidepressants for management of residual symptoms in inflammatory bowel disease. J Clin Gastroenterol 2014; 48: 423-429
17 Jackson JL, O’Malley PG, Tomkins G. et al. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. Am J Med 2000; 108: 65-72
18 Rahimi R, Nikfar S, Rezaie A. et al. Efficacy of tricyclic antidepressants in irritable bowel syndrome: a meta-analysis. World J Gastroenterol 2009; 15: 1548-1553
19 Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet 2002; 360: 1155-1162
20 Wang B, Yang LP, Zhang XZ. et al. New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme. Drug Metab Rev 2009; 41: 573-643
21 Wang X, Li J, Dong G. et al. The endogenous substrates of brain CYP2D. Eur J Pharmacol 2014; 724: 211-218
22 Owen RP, Sangkuhl K, Klein TE. et al. Cytochrome P450 2D6. Pharmacogenet Genomics 2009; 19: 559-562
23 Camilleri M. The role of pharmacogenetics in nonmalignant gastrointestinal diseases. Nat Rev Gastroenterol Hepatol 2012; 9: 173-184
24 Caudle KE, Sangkuhl K, Whirl-Carrillo M. et al. Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clin Transl Sci 2020; 13: 116-124
25 Ingelman-Sundberg M, Sim SC, Gomez A. et al. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 2007; 116: 496-526
26 Kale E, Sen A. Characterization of Human CYP450 Isozymes Responsible for the In Vitro Oxidative Metabolism of Mesalamine Used for Colitis. J Innov. Sci Educ 2019; 7: 753-759
27 RDKit: Open-source cheminformatics. [Available from https://www.rdkit.org]
28 Landrum G, Landrum G. RDKit: A software suite for cheminformatics, computational chemistry, and predictive modeling 2013
29 RCSB PDB: Homepage. [Available from https://www.rcsb.org/]
30 Berman HM, Westbrook J, Feng Z. et al. The Protein Data Bank. Nucleic Acids Res 2000; 28: 235-242
31 GitHub – openmm/pdbfixer: PDBFixer fixes problems in PDB files [Available from https://github.com/openmm/pdbfixer]
32 Eastman P, Swails J, Chodera JD. et al. OpenMM 7: Rapid development of high performance algorithms for molecular dynamics. PLoS Comput Biol 2017; 13: e1005659
33 Le Guilloux V, Schmidtke P, Tuffery P. Fpocket: an open source platform for ligand pocket detection. BMC Bioinformatics 2009; 10: 168
34 Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31: 455-461
35 Eberhardt J, Santos-Martins D, Tillack AF. et al. AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. J Chem Inf Model 2021; 61: 3891-3898
36 Van Der Spoel D, Lindahl E, Hess B. et al. GROMACS: fast, flexible, and free. J Comput Chem 2005; 26: 1701-1718
37 Kumari R, Kumar R. Open Source Drug Discovery C, Lynn A. g_mmpbsa--a GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model 2014; 54: 1951-1962
38 Chauret N, Dobbs B, Lackman RL. et al. The use of 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin (AMMC) as a specific CYP2D6 probe in human liver microsomes. Drug Metab Dispos 2001; 29: 1196-1200
39 Davydov DR, Davydova NY, Rodgers JT. et al. Toward a systems approach to the human cytochrome P450 ensemble: interactions between CYP2D6 and CYP2E1 and their functional consequences. Biochem J 2017; 474: 3523-3542
40 Gu GZ, Xia HM, Pang ZQ. et al. Determination of sulphasalazine and its main metabolite sulphapyridine and 5-aminosalicylic acid in human plasma by liquid chromatography/tandem mass spectrometry and its application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2011; 879: 449-456
41 Mahmud N, Weir DG, Kelleher D. Systemic levels of free 5-aminosalicylic acid depend on the nature of the 5-aminosalicyclic acid derivative and not on disease activity or extent in patients with inflammatory bowel disease. Ir J Med Sci 1999; 168: 228-232
42 Ham M, Moss AC. Mesalamine in the treatment and maintenance of remission of ulcerative colitis. Expert Rev Clin Pharmacol 2012; 5: 113-123
43 Stresser DM, Turner SD, Blanchard AP. et al. Cytochrome P450 fluorometric substrates: identification of isoform-selective probes for rat CYP2D2 and human CYP3A4. Drug Metab Dispos 2002; 30: 845-852
44 Otton SV, Wu D, Joffe RT. et al. Inhibition by fluoxetine of cytochrome P450 2D6 activity. Clin Pharmacol Ther 1993; 53: 401-409
45 Ganesh AN, Donders EN, Shoichet BK. et al. Colloidal aggregation: from screening nuisance to formulation nuance. Nano Today 2018; 19: 188-200
46 Li H, Sheng Y, Li W. et al. Recent Advances in Molecular Fluorescent Probes for CYP450 Sensing and Imaging. Chemosensors 2022; 10: 304
47 Xu S, Xing X, Liu Y. et al. A hemicyanine-based fluorescence probe for selective detection of CYP2D6 in living cells and tumor-bearing mice. Dyes and Pigments 2022; 198: 109959
48 Nelson DR, Koymans L, Kamataki T. et al. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1996; 6: 1-42
49 Li Q, Wang R, Guo Y. et al. Relationship of CYP2D6 genetic polymorphisms and the pharmacokinetics of tramadol in Chinese volunteers. J Clin Pharm Ther 2010; 35: 239-247
50 Travis SP. Which 5-ASA?. Gut 2002; 51: 548-549
51 Pastorini E, Locatelli M, Simoni P. et al. Development and validation of a HPLC-ESI-MS/MS method for the determination of 5-aminosalicylic acid and its major metabolite N-acetyl-5-aminosalicylic acid in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2008; 872: 99-106
52 Nobilis M, Vybiralova Z, Sladkova K. et al. High-performance liquid-chromatographic determination of 5-aminosalicylic acid and its metabolites in blood plasma. J Chromatogr A 2006; 1119: 299-308