{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:40:06Z","timestamp":1760150406128,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,4]],"date-time":"2023-11-04T00:00:00Z","timestamp":1699056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical University of Lublin","award":["DS8\/21"],"award-info":[{"award-number":["DS8\/21"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Understanding the metabolism of pharmaceutical compounds is a fundamental prerequisite for ensuring their safety and efficacy in clinical use. However, conventional methods for monitoring drug metabolism often come with the drawbacks of being time-consuming and costly. In an ongoing quest for innovative approaches, the application of electrochemistry in metabolism studies has gained prominence as a promising approach for the synthesis and analysis of drug transformation products. In this study, we investigated the hepatic metabolism of voriconazole, an antifungal medication, by utilizing human liver microsomes (HLM) assay coupled with LC-MS. Based on the obtained results, the electrochemical parameters were optimized to simulate the biotransformation reactions. Among the various electrodes tested, the chemometric analysis revealed that the iron(II) phthalocyanine electrode was the most effective in catalyzing the formation of all hepatic voriconazole metabolites. These findings exemplify the potential of phthalocyanine electrodes as an efficient and cost-effective tool for simulating the intricate metabolic processes involved in drug biotransformation, offering new possibilities in the field of pharmaceutical research. Additionally, in silico analysis showed that two detected metabolites may exhibit significantly higher acute toxicity and mutagenic potential than the parent compound.<\/jats:p>","DOI":"10.3390\/pharmaceutics15112586","type":"journal-article","created":{"date-parts":[[2023,11,4]],"date-time":"2023-11-04T14:51:01Z","timestamp":1699109461000},"page":"2586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Electrochemical Simulation of Phase I Hepatic Metabolism of Voriconazole Using a Screen-Printed Iron(II) Phthalocyanine Electrode"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6439-9127","authenticated-orcid":false,"given":"Micha\u0142","family":"Wro\u0144ski","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8353-1859","authenticated-orcid":false,"given":"Jakub","family":"Trawi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8429-7515","authenticated-orcid":false,"given":"Robert","family":"Skibi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1080\/03602532.2019.1632888","article-title":"Novel Insights into the Complex Pharmacokinetics of Voriconazole: A Review of Its Metabolism","volume":"51","author":"Schulz","year":"2019","journal-title":"Drug Metab. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1124\/dmd.109.030676","article-title":"Investigation into UDP-Glucuronosyltransferase (UGT) Enzyme Kinetics of Imidazole- and Triazole-Containing Antifungal Drugs in Human Liver Microsomes and Recombinant UGT Enzymes","volume":"38","author":"Bourcier","year":"2010","journal-title":"Drug Metab. Dispos."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1124\/dmd.31.6.731","article-title":"The Disposition of Voriconazole in Mouse, Rat, Rabbit, Guinea Pig, Dog, And Human","volume":"31","author":"Roffey","year":"2003","journal-title":"Drug Metab. Dispos."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1111\/bjd.13862","article-title":"Voriconazole N-Oxide and Its Ultraviolet B Photoproduct Sensitize Keratinocytes to Ultraviolet A","volume":"173","author":"Ona","year":"2015","journal-title":"Br. J. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1007\/s12010-009-8689-6","article-title":"Role of Human Liver Microsomes in In Vitro Metabolism of Drugs\u2014A Review","volume":"160","author":"Asha","year":"2010","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"196","DOI":"10.4172\/2157-7609.1000196","article-title":"The Role of Biotransformation in Drug Discovery and Development","volume":"6","author":"Kebamo","year":"2015","journal-title":"J. Drug Metab. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1021\/acsmedchemlett.0c00202","article-title":"Biotransformation: Impact and Application of Metabolism in Drug Discovery","volume":"11","author":"Evans","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Calderon, L. (2012). Chromatography\u2013The Most Versatile Method of Chemical Analysis, InTech.","DOI":"10.5772\/2707"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ahmad, U. (2023). Dosage Forms\u2013Innovation and Future Perspectives, IntechOpen.","DOI":"10.5772\/intechopen.95734"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.aca.2014.05.017","article-title":"Electrochemistry\/Mass Spectrometry as a Tool in Metabolism Studies\u2014A Review","volume":"834","author":"Faber","year":"2014","journal-title":"Anal. Chim. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.jpba.2019.03.017","article-title":"Electrochemical Simulation of Metabolism for Antitumor-Active Imidazoacridinone C-1311 and in Silico Prediction of Drug Metabolic Reactions","volume":"169","author":"Mazerska","year":"2019","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.trac.2015.01.016","article-title":"Electrosynthesis Methods and Approaches for the Preparative Production of Metabolites from Parent Drugs","volume":"70","author":"Gul","year":"2015","journal-title":"TrAC Trends Anal. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s00604-015-1651-0","article-title":"Screen-Printed Electrodes for Environmental Monitoring of Heavy Metal Ions: A Review","volume":"183","author":"Barton","year":"2016","journal-title":"Microchim. Acta"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.mimet.2013.08.014","article-title":"Application of an ELISA-Type Screen Printed Electrode-Based Potentiometric Assay to the Detection of Cryptosporidium Parvum Oocysts","volume":"95","author":"Laczka","year":"2013","journal-title":"J. Microbiol. Methods"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mincu, N.-B., Lazar, V., Stan, D., Mihailescu, C.M., Iosub, R., and Mateescu, A.L. (2020). Screen-Printed Electrodes (SPE) for In Vitro Diagnostic Purpose. Diagnostics, 10.","DOI":"10.3390\/diagnostics10080517"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"39","DOI":"10.30958\/ajs.5-1-3","article-title":"Electrochemistry of Eugenol and Its Metabolism on a Bare Screen-Printed Electrode","volume":"5","author":"Vasiliadou","year":"2018","journal-title":"Athens J. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1139\/cjc-2017-0279","article-title":"Simulating the Phase II Metabolism of Raloxifene on a Screen-Printed Electrode","volume":"95","author":"Vasiliadou","year":"2017","journal-title":"Can. J. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.1002\/elan.201100355","article-title":"Utility of Screen Printed Electrodes for in Vitro Metabolic Stability Assays: Application to Acetaminophen and Its Thioconjugates","volume":"23","author":"Kauffmann","year":"2011","journal-title":"Electroanalysis"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/BF00547422","article-title":"Isolation of Human Hepatic Microsomes and Their Inhibition by Cimetidine and Ranitidine","volume":"29","author":"Hoensch","year":"1985","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2607","DOI":"10.4155\/bio.14.166","article-title":"Electrochemical Simulation of Phase I Metabolism for 21 Drugs Using Four Different Working Electrodes in an Automated Screening Setup with MS Detection","volume":"6","author":"Ambach","year":"2014","journal-title":"Bioanalysis"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1097\/FPC.0000000000000276","article-title":"PharmGKB Summary: Voriconazole Pathway, Pharmacokinetics","volume":"27","author":"Barbarino","year":"2017","journal-title":"Pharmacogenet. Genom."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Schulz, J., Thomas, A., Saleh, A., Mikus, G., Kloft, C., and Michelet, R. (2022). Towards the Elucidation of the Pharmacokinetics of Voriconazole: A Quantitative Characterization of Its Metabolism. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14030477"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1124\/dmd.107.019646","article-title":"Role of Flavin-Containing Monooxygenase in Oxidative Metabolism of Voriconazole by Human Liver Microsomes","volume":"36","author":"Yanni","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lee, P.W., Aizawa, H., Gan, L.L., Prakash, C., and Zhong, D. (2014). Handbook of Metabolic Pathways of Xenobiotics, Wiley.","DOI":"10.1002\/9781118541203"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1016\/j.bcp.2007.03.012","article-title":"Roles of CYP3A4 and CYP2C19 in Methyl Hydroxylated and N-Oxidized Metabolite Formation from Voriconazole, a New Anti-Fungal Agent, in Human Liver Microsomes","volume":"73","author":"Murayama","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1080\/10590501.2014.938955","article-title":"Evaluation of QSAR Models for the Prediction of Ames Genotoxicity: A Retrospective Exercise on the Chemical Substances Registered Under the EU Reach Regulation","volume":"32","author":"Cassano","year":"2014","journal-title":"J. Environ. Sci. Health Part C"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.taap.2010.10.024","article-title":"Assessing the Toxic Effects of Ethylene Glycol Ethers Using Quantitative Structure Toxicity Relationship Models","volume":"254","author":"Ruiz","year":"2011","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1080\/10590501.2013.763576","article-title":"Comparison of In Silico Models for Prediction of Mutagenicity","volume":"31","author":"Bakhtyari","year":"2013","journal-title":"J. Environ. Sci. Health Part C"},{"key":"ref_29","unstructured":"EMA (2023, October 20). Vfend. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/vfend."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/11\/2586\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:17:36Z","timestamp":1760131056000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/11\/2586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,4]]},"references-count":29,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["pharmaceutics15112586"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15112586","relation":{},"ISSN":["1999-4923"],"issn-type":[{"type":"electronic","value":"1999-4923"}],"subject":[],"published":{"date-parts":[[2023,11,4]]}}}