{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T06:45:40Z","timestamp":1782801940965,"version":"3.54.5"},"reference-count":46,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Traditional genotype-guided dosing often fails to predict real-time variability in the metabolic phenotype during complex polypharmacy. This secondary analysis of a retrospective cohort aims to elucidate mechanisms underlying real-time phenoconversion during antipsychotic therapy, focusing on homozygous loss-of-function CYP3A5*3\/*3 non-expressors. Methods: Using an additive phenoconversion model that integrates a genotype-derived baseline with environmental modifiers for drug\u2013drug interactions (DDI), systemic inflammation (CRP), and renal function (eGFR), we demonstrate that the expressed metabolic phenotype is a dynamic, context-dependent construct that can markedly diverge from the genotype-predicted state. Objectives: Our data show that patients with CYP3A5*3\/*3 and CYP3A inhibitors (e.g., ritonavir) had a quetiapine plasma concentrations reached 1850 ng\/mL, corresponding to 3.7-fold above the internationally accepted therapeutic reference range of 100\u2013500 ng\/mL. Acute systemic inflammation (CRP &gt; 50 mg\/L) induced a functional poor metabolizer phenotype (Pact &lt; \u22120.9) in individuals with a genotypic normal metabolizer status. In contrast, strong inducers such as carbamazepine, phenytoin, and heavy smoking promoted an ultra-rapid metabolizer state (CLind &gt; 4.0 L\/h, quetiapine &lt; 30 ng\/mL), consistent with treatment failure. In this cohort, the additive Pact model showed a strong association with observed clearance and identified clinically relevant phenoconversion mechanisms not predicted from genotype alone. Conclusions: These results support a dynamic, multi-parametric approach that integrates pharmacogenomics, therapeutic drug monitoring, biomarker profiling (CRP, eGFR), and structured DDI assessment to enable higher-resolution, real-time phenotype tracking and more informed dose individualization in high-risk psychiatric polypharmacy.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070782","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:58:04Z","timestamp":1782799084000},"page":"782","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synergistic Effects of Inflammation and Drug Interactions on CYP3A5*3\/*3 Phenoconversion in Antipsychotic Metabolism"],"prefix":"10.3390","volume":"18","author":[{"given":"Krisztina","family":"K\u0151halmy","sequence":"first","affiliation":[{"name":"Independent Researcher, 2040 Buda\u00f6rs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2948-1327","authenticated-orcid":false,"given":"Ayaan","family":"Borthakur","sequence":"additional","affiliation":[{"name":"Independent Researcher, Guwahati 781028, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6554-0304","authenticated-orcid":false,"given":"P\u00e1lma","family":"Porrogi","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Sz\u00e9chenyi Istv\u00e1n University, 9026 Gy\u0151r, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/bcp.12441","article-title":"Addressing Phenoconversion: The Achilles\u2019 Heel of Personalized Medicine","volume":"79","author":"Shah","year":"2015","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.jad.2024.10.112","article-title":"Effect of CYP3A5*3 Genotype on Exposure and Efficacy of Quetiapine: A Retrospective, Cohort Study","volume":"370","author":"Zhao","year":"2025","journal-title":"J. Affect. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1124\/dmd.108.023291","article-title":"Metabolism of Quetiapine by CYP3A4 and CYP3A5 in Presence or Absence of Cytochrome B5","volume":"37","author":"Bakken","year":"2009","journal-title":"Drug Metab. Dispos."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Klomp, S.D., Manson, M.L., Guchelaar, H.-J., and Swen, J.J. (2020). Phenoconversion of Cytochrome P450 Metabolism: A Systematic Review. J. Clin. Med., 9.","DOI":"10.3390\/jcm9092890"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Mostafa, S., Polasek, T.M., Sheffield, L.J., Huppert, D., and Kirkpatrick, C.M.J. (2021). Quantifying the Impact of Phenoconversion on Medications With Actionable Pharmacogenomic Guideline Recommendations in an Acute Aged Persons Mental Health Setting. Front. Psychiatry, 12.","DOI":"10.3389\/fpsyt.2021.724170"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"de Jong, L.M., Jiskoot, W., Swen, J.J., and Manson, M.L. (2020). Distinct Effects of Inflammation on Cytochrome P450 Regulation and Drug Metabolism: Lessons from Experimental Models and a Potential Role for Pharmacogenetics. Genes, 11.","DOI":"10.3390\/genes11121509"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1055\/s-0037-1600991","article-title":"Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017","volume":"51","author":"Hiemke","year":"2018","journal-title":"Pharmacopsychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Biso, L., Aringhieri, S., Carli, M., Scarselli, M., and Longoni, B. (2024). Therapeutic Drug Monitoring in Psychiatry: Enhancing Treatment Precision and Patient Outcomes. Pharmaceuticals, 17.","DOI":"10.3390\/ph17050642"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Lenoir, C., Rollason, V., Desmeules, J.A., and Samer, C.F. (2021). Influence of Inflammation on Cytochromes P450 Activity in Adults: A Systematic Review of the Literature. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.733935"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1097\/FPC.0000000000000183","article-title":"CYP3A4 Intronic SNP Rs35599367 (CYP3A4*22) Alters RNA Splicing","volume":"26","author":"Wang","year":"2016","journal-title":"Pharmacogenetics Genom."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mulder, T.A.M., van Eerden, R.A.G., de With, M., Elens, L., Hesselink, D.A., Matic, M., Bins, S., Mathijssen, R.H.J., and van Schaik, R.H.N. (2021). CYP3A4\u221722 Genotyping in Clinical Practice: Ready for Implementation?. Front. Genet., 12.","DOI":"10.3389\/fgene.2021.711943"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1016\/S0149-2918(08)80047-1","article-title":"Clinically Relevant Pharmacokinetic Drug Interactions with Second-Generation Antidepressants: An Update","volume":"30","author":"Spina","year":"2008","journal-title":"Clin. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1124\/dmd.114.061093","article-title":"Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine","volume":"43","author":"Shah","year":"2015","journal-title":"Drug Metab. Dispos."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s12272-026-01599-9","article-title":"JAK2\/STAT3-Dependent Regulation of MDM4\/MDM2-P53 Signaling in Methotrexate-Induced Ferroptosis and Nephrotoxicity","volume":"49","author":"Cheng","year":"2026","journal-title":"Arch. Pharm. Res."},{"key":"ref_15","first-page":"1646","article-title":"The Transcription Factor HNF-4\u03b1: A Key Player in Haematological Disorders","volume":"19","author":"Belali","year":"2023","journal-title":"Arch. Med. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s13148-018-0512-1","article-title":"DNA Methylation and Repressive H3K9 and H3K27 Trimethylation in the Promoter Regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 Genes in Human Primary Breast Cancer","volume":"10","author":"Taha","year":"2018","journal-title":"Clin. Epigenetics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1002\/jcp.30579","article-title":"Dynamic Alterations of H3K4me3 and H3K27me3 at ADAM17 and Jagged-1 Gene Promoters Cause an Inflammatory Switch of Endothelial Cells","volume":"237","author":"Katakia","year":"2022","journal-title":"J. Cell. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Szczepanek, J., and Tretyn, A. (2023). MicroRNA-Mediated Regulation of Histone-Modifying Enzymes in Cancer: Mechanisms and Therapeutic Implications. Biomolecules, 13.","DOI":"10.3390\/biom13111590"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.mam.2009.04.002","article-title":"Nuclear Receptors CAR and PXR: Molecular, Functional, and Biomedical Aspects","volume":"30","author":"Ascenzi","year":"2009","journal-title":"Mol. Asp. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"17882","DOI":"10.1074\/jbc.M601302200","article-title":"Role of NF-kappaB in Regulation of PXR-Mediated Gene Expression: A Mechanism for the Suppression of Cytochrome P-450 3A4 by Proinflammatory Agents","volume":"281","author":"Gu","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Aly, S.M., Hennart, B., Gaulier, J.-M., and Allorge, D. (2024). Effect of CYP2D6, 2C19, and 3A4 Phenoconversion in Drug-Related Deaths. Toxics, 12.","DOI":"10.3390\/toxics12040260"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zubiaur, P., Fern\u00e1ndez-Campos, P., Navares-G\u00f3mez, M., Soria-Chacartegui, P., Villapalos-Garc\u00eda, G., Rom\u00e1n, M., Mej\u00eda-Abril, G., Ochoa, D., and Abad-Santos, F. (2021). Variants in COMT, CYP3A5, CYP2B6, and ABCG2 Alter Quetiapine Pharmacokinetics. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13101573"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.taap.2004.01.010","article-title":"The Effects of Gender, Age, Ethnicity, and Liver Cirrhosis on Cytochrome P450 Enzyme Activity in Human Liver Microsomes and Inducibility in Cultured Human Hepatocytes","volume":"199","author":"Parkinson","year":"2004","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Molla, G., and Bitew, M. (2024). Revolutionizing Personalized Medicine: Synergy with Multi-Omics Data Generation, Main Hurdles, and Future Perspectives. Biomedicines, 12.","DOI":"10.3390\/biomedicines12122750"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"35","DOI":"10.9740\/mhc.2016.01.035","article-title":"A review of significant pharmacokinetic drug interactions with antidepressants and their management","volume":"6","author":"Hoffelt","year":"2016","journal-title":"Ment. Health Clin."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1097\/00004714-200702000-00005","article-title":"Comparison of Duloxetine, Escitalopram, and Sertraline Effects on Cytochrome P450 2D6 Function in Healthy Volunteers","volume":"27","author":"Preskorn","year":"2007","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1007\/s11920-012-0284-9","article-title":"Clinically Significant Psychotropic Drug-Drug Interactions in the Primary Care Setting","volume":"14","author":"English","year":"2012","journal-title":"Curr. Psychiatry Rep."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gandia, P., Decheiver, S., Picard, M., Guilhaumou, R., Baklouti, S., and Concordet, D. (2023). Hypoalbuminemia and Pharmacokinetics: When the Misunderstanding of a Fundamental Concept Leads to Repeated Errors over Decades. Antibiotics, 12.","DOI":"10.3390\/antibiotics12030515"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S0009-9236(03)00015-8","article-title":"Cytochrome P4502C9 Activity in End-Stage Renal Disease","volume":"73","author":"Dreisbach","year":"2003","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100880","DOI":"10.1016\/j.jhepr.2023.100880","article-title":"Burden of Grade 3 or 4 Liver Injury Associated with Immune Checkpoint Inhibitors","volume":"5","author":"Parlati","year":"2023","journal-title":"JHEP Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0378-4274(00)00310-6","article-title":"Cytokine-Mediated Suppression of Cytochrome P450 1A1 in Hepa-1c1c7 Cells by Pokeweed Mitogen","volume":"119","author":"Jeong","year":"2001","journal-title":"Toxicol. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"109056","DOI":"10.1016\/j.cbi.2020.109056","article-title":"Cytochrome P450 2E1 and Its Roles in Disease","volume":"322","author":"Guengerich","year":"2020","journal-title":"Chem. Biol. Interact."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Harjum\u00e4ki, R., Pridgeon, C.S., and Ingelman-Sundberg, M. (2021). CYP2E1 in Alcoholic and Non-Alcoholic Liver Injury. Roles of ROS, Reactive Intermediates and Lipid Overload. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22158221"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1002\/cpt.147","article-title":"Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors","volume":"98","author":"Hicks","year":"2015","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1038\/s41431-023-01347-3","article-title":"Dutch Pharmacogenetics Working Group (DPWG) Guideline for the Gene-Drug Interaction between CYP2D6, CYP3A4 and CYP1A2 and Antipsychotics","volume":"32","author":"Beunk","year":"2024","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Mouliou, D.S. (2023). C-Reactive Protein: Pathophysiology, Diagnosis, False Test Results and a Novel Diagnostic Algorithm for Clinicians. Diseases, 11.","DOI":"10.3390\/diseases11040132"},{"key":"ref_37","first-page":"e3868","article-title":"Evaluation of Serum Interleukin-6 and C-Reactive Protein Levels in Drug-Na\u00efve Major Depressive Disorder Patients","volume":"11","author":"Nishuty","year":"2019","journal-title":"Cureus"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"World Medical Association (2013). World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA, 310, 2191\u20132194.","DOI":"10.1001\/jama.2013.281053"},{"key":"ref_39","first-page":"2565","article-title":"NanoDrop Microvolume Quantitation of Nucleic Acids","volume":"45","author":"Desjardins","year":"2010","journal-title":"J. Vis. Exp."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/gim.2016.87","article-title":"Standardizing Terms for Clinical Pharmacogenetic Test Results: Consensus Terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC)","volume":"19","author":"Caudle","year":"2017","journal-title":"Genet. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1002\/cpt.910","article-title":"The Pharmacogene Variation (PharmVar) Consortium: Incorporation of the Human Cytochrome P450 (CYP) Allele Nomenclature Database","volume":"103","author":"Gaedigk","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S1050-3862(98)00019-9","article-title":"Allelic Discrimination Using Fluorogenic Probes and the 5\u2032 Nuclease Assay","volume":"14","author":"Livak","year":"1999","journal-title":"Genet. Anal."},{"key":"ref_43","unstructured":"European Medicines Agency (EMA) (2026, February 23). Bioanalytical Method Validation\u2014Scientific Guideline. Available online: https:\/\/www.ema.europa.eu\/en\/bioanalytical-method-validation-scientific-guideline."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1124\/dmd.107.020065","article-title":"The Influence of CYP3A5 Genotype on Dexamethasone Induction of CYP3A Activity in African Americans","volume":"36","author":"Roberts","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1124\/dmd.115.064998","article-title":"Variability in Expression of CYP3A5 in Human Fetal Liver","volume":"43","author":"Vyhlidal","year":"2015","journal-title":"Drug Metab. Dispos."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2217\/pgs.12.187","article-title":"CYP3A4*22: Promising Newly Identified CYP3A4 Variant Allele for Personalizing Pharmacotherapy","volume":"14","author":"Elens","year":"2013","journal-title":"Pharmacogenomics"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/7\/782\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T06:09:06Z","timestamp":1782799746000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/7\/782"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":46,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["pharmaceutics18070782"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18070782","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,26]]}}}