{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:33:33Z","timestamp":1790127213760,"version":"4.0.1"},"reference-count":82,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T00:00:00Z","timestamp":1745539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Salud Carlos III (ISCIII)"},{"name":"European Union funds"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Methadone maintenance treatment (MMT) is widely used in opioid use disorder (OUD). Its efficacy is influenced by its metabolism, primarily mediated by Cytochrome P450 (CYP450) enzymes in the liver. Genetic polymorphisms in CYP450 genes and other factors, such as age, sex, and concomitant treatments, contribute to interindividual variability in methadone response. This article addresses the relevance of pharmacokinetic biomarkers in methadone metabolism and its impact on treatment outcomes in European populations over the past 25 years. Methods: A systematic review was conducted using four databases (PsycINFO, PubMed, Scopus, and Web of Science) for studies published between 2000 and 2024 following the PRISMA 2020 guidelines (CRD42025641373 in PROSPERO). Two independent reviewers screened and assessed the study quality using NHLBI tools. Discrepancies were solved through consensus. Relevant data including sample size, genetic biomarkers, and key findings were extracted for each study. Data were synthesized and described in detail. Results: Fourteen studies on pharmacogenetic biomarkers influencing methadone metabolism in European populations were analyzed, encompassing a total of 3180 subjects. CYP2B6*6 was identified as a key variant associated with increased (S)-methadone plasma levels, potentially leading to cardiac complications, while the role of other pharmacokinetic genes, including ABCB1 and CYP2D6, was inconclusive. Conclusions: Genetic polymorphisms significantly influence methadone metabolism, with the CYP2B6*6 allele playing a key role in (S)-methadone metabolism and associated with cardiac risks. Pharmacogenetic studies integrating co-mediation\u2014the principal cause of phenoconversion\u2014as a potential variable alongside gender differences and encompassing adequate sample sizes could improve outcomes and establish the basis for personalized medicine of MMT.<\/jats:p>","DOI":"10.3390\/ph18050623","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T08:02:57Z","timestamp":1745568177000},"page":"623","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Relevance of Pharmacokinetic Biomarkers in Response to Methadone Treatment: A Systematic Review"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1623-1110","authenticated-orcid":false,"given":"Sheila","family":"Recarey-Rama","sequence":"first","affiliation":[{"name":"Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"},{"name":"Pharmacogenomics and Drug Discovery Group (GenDeM), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"G\u00f3mez-Trigo","sequence":"additional","affiliation":[{"name":"Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"},{"name":"Pharmacogenomics and Drug Discovery Group (GenDeM), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"},{"name":"Psychiatry Service, University Hospital Complex of Santiago de Compostela, Galician Health System (SERGAS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7637-6915","authenticated-orcid":false,"given":"Almudena","family":"Gil-Rodriguez","sequence":"additional","affiliation":[{"name":"Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"},{"name":"Pharmacogenomics and Drug Discovery Group (GenDeM), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3359-5867","authenticated-orcid":false,"given":"Eduardo","family":"Dominguez","sequence":"additional","affiliation":[{"name":"Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s","family":"S\u00e1nchez-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngela","family":"Riveiro-Recimil","sequence":"additional","affiliation":[{"name":"Genetics Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alba","family":"Barral-Ra\u00f1a","sequence":"additional","affiliation":[{"name":"Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"},{"name":"Pharmacogenomics and Drug Discovery Group (GenDeM), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7756-2314","authenticated-orcid":false,"given":"Jose","family":"de Leon","sequence":"additional","affiliation":[{"name":"Mental Health Research Center at Eastern State Hospital, University of Kentucky, Lexington, KY 40511, USA"},{"name":"Neuroscience Investigation Group (CTS-549), Neuroscience Institute, University of Granada, 18016 Granada, Spain"},{"name":"Centre for Biomedical Network Research on Mental Health (CIBERSAM), Santiago Ap\u00f3stol Hospital, University of Basque Country, 01004 Vitoria, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Rodriguez-Viyuela","sequence":"additional","affiliation":[{"name":"Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"},{"name":"Pharmacogenomics and Drug Discovery Group (GenDeM), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Arrojo","sequence":"additional","affiliation":[{"name":"Psychiatry Service, University Hospital Complex of Santiago de Compostela, Galician Health System (SERGAS), 15706 Santiago de Compostela, Spain"},{"name":"Psychiatric Genetics Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1085-8986","authenticated-orcid":false,"given":"Angel","family":"Carracedo","sequence":"additional","affiliation":[{"name":"Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"},{"name":"Genetics Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"},{"name":"Galician Public Foundation of Genomic Medicine (FPGMX), Galician Healthcare Service (SERGAS), 15706 Santiago de Compostela, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olalla","family":"Maro\u00f1as","sequence":"additional","affiliation":[{"name":"Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"},{"name":"Pharmacogenomics and Drug Discovery Group (GenDeM), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"},{"name":"Galician Public Foundation of Genomic Medicine (FPGMX), Galician Healthcare Service (SERGAS), 15706 Santiago de Compostela, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/S0885-3924(03)00219-7","article-title":"Definitions related to the medical use of opioids: Evolution towards universal agreement","volume":"26","author":"Savage","year":"2003","journal-title":"J. Pain. Symptom Manag."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1038\/nn1105-1442","article-title":"Plasticity of reward neurocircuitry and the \u2018dark side\u2019 of drug addiction","volume":"8","author":"Koob","year":"2005","journal-title":"Nat. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1749-6632.2011.06298.x","article-title":"The clinical significance of drug craving","volume":"1248","author":"Tiffany","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_4","first-page":"e13173","article-title":"Opioid Use Disorder: Treatments and Barriers","volume":"13","author":"Patel","year":"2021","journal-title":"Cureus"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.neuron.2015.11.027","article-title":"Common Brain Mechanisms of Chronic Pain and Addiction","volume":"89","author":"Elman","year":"2016","journal-title":"Neuron"},{"key":"ref_6","first-page":"1","article-title":"Opioid use disorder","volume":"6","author":"Strang","year":"2020","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Elman, I., Howard, M., Borodovsky, J.T., Mysels, D., Rott, D., Borsook, D., and Albanese, M. (2020). Metabolic and Addiction Indices in Patients on Opioid Agonist Medication-Assisted Treatment: A Comparison of Buprenorphine and Methadone. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-62556-0"},{"key":"ref_8","unstructured":"United Nations: Office on Drugs and Crime (2025, January 26). World Drug Report 2024\u2014Special Points of Interest. Available online: www.unodc.org\/unodc\/en\/data-and-analysis\/wdr2024-special-points-of-interest.html."},{"key":"ref_9","unstructured":"Ministerio de Sanidad, Consumo y Bienestar Social (2025, January 26). Memoria Plan Nacional sobre Drogas 2017. Disponible en. Available online: https:\/\/pnsd.sanidad.gob.es\/pnsd\/memorias\/docs\/2019_MEMORIA_2017.pdf."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.chc.2016.03.002","article-title":"Opioid Use Disorders","volume":"25","author":"Sharma","year":"2016","journal-title":"Child Adolesc. Psychiatr. Clin."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Panday, S.K., Shankar, V., Lyman, R.A., and Alexov, E. (2024). Genetic Variants Linked to Opioid Addiction: A Genome-Wide Association Study. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202410.0378.v1"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.biopsych.2013.08.034","article-title":"Genome-wide association study of opioid dependence: Multiple associations mapped to calcium and potassium pathways","volume":"76","author":"Gelernter","year":"2014","journal-title":"Biol. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1146\/annurev.psych.59.103006.093548","article-title":"Addiction and the brain antireward system","volume":"59","author":"Koob","year":"2008","journal-title":"Annu. Rev. Psychol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"109551","DOI":"10.1016\/j.drugalcdep.2022.109551","article-title":"Prevalence of mental disorders among people with opioid use disorder: A systematic review and meta-analysis","volume":"238","author":"Santo","year":"2022","journal-title":"Drug Alcohol Depend."},{"key":"ref_15","first-page":"3","article-title":"Comorbidity in Opioid Addiction: A Brief Review","volume":"12","author":"Altable","year":"2023","journal-title":"J. Drug Alcohol. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1176\/appi.prcp.20180006","article-title":"Pharmacological and Behavioral Treatment of Opioid Use Disorder","volume":"1","author":"Sofuoglu","year":"2018","journal-title":"Psychiatr. Res. Clin. Pr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1080\/10550881003684798","article-title":"Pharmacotherapy in the Treatment of Addiction: Methadone","volume":"29","author":"Kreek","year":"2010","journal-title":"J. Addict. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1080\/17581869.2025.2457316","article-title":"The effect of oral methadone on the QTc interval in cancer pain patients","volume":"15","author":"Sheen","year":"2025","journal-title":"Pain Manag."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1053\/j.jvca.2024.11.012","article-title":"Intraoperative Methadone in Adult Cardiac Surgical Patients and Risks for Postoperative QTc Prolongation","volume":"39","author":"McClain","year":"2024","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1111\/bph.14105","article-title":"Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: Link to clinical reports of serotonin syndrome","volume":"175","author":"Rickli","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_21","unstructured":"National Academies of Sciences, Engineering, and Medicine, Action Collaborative on Countering the U.S. Opioid Epidemic, Health and Medicine Division, Board on Health Care Services, Board on Health Sciences Policy, Stroud, C., Posey Norris, S.M., and Bain, L. (2025, January 26). The History of Methadone and Barriers to Access for Different Populations, Methadone Treatment for Opioid Use Disorder: Improving Access Through Regulatory and Legal Change: Proceedings of a Workshop, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK585210\/."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.jpain.2020.04.004","article-title":"Methadone in Pain Management: A Systematic Review","volume":"22","author":"Hanna","year":"2021","journal-title":"J. Pain"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/j.1742-7843.2010.00628.x","article-title":"Stereo-Selective Metabolism of Methadone by Human Liver Microsomes and cDNA-Expressed Cytochrome P450s: A Reconciliation","volume":"108","author":"Chang","year":"2011","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1111\/j.1399-6576.2008.01597.x","article-title":"Clinical pharmacology of methadone for pain","volume":"52","author":"Fredheim","year":"2008","journal-title":"Acta Anaesthesiol. Scand."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/chir.10303","article-title":"Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19","volume":"16","author":"Gerber","year":"2004","journal-title":"Chirality"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1097\/ALN.0b013e3181642938","article-title":"Role of CYP2B6 in stereoselective human methadone metabolism","volume":"108","author":"Totah","year":"2008","journal-title":"Anesthesiology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.2165\/00003088-200241140-00003","article-title":"Interindividual Variability of the Clinical Pharmacokinetics of Methadone","volume":"41","author":"Eap","year":"2002","journal-title":"Clin. Pharmacokinet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/BF03256276","article-title":"Interindividual Variability of Methadone Response","volume":"12","author":"Li","year":"2008","journal-title":"Mol. Diagn. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"977","DOI":"10.2217\/pgs.14.19","article-title":"Assessment of CYP450 Genetic Variability Effect on Methadone Dose and Tolerance","volume":"15","author":"Tsai","year":"2014","journal-title":"Pharmacogenomics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.drugalcdep.2014.10.014","article-title":"Ethnic and genetic factors in methadone pharmacokinetics: A population pharmacokinetic study","volume":"145","author":"Bart","year":"2014","journal-title":"Drug Alcohol. Depend."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1093\/jat\/bku091","article-title":"Fatal methadone toxicity: Potential role of CYP3A4 genetic polymorphism","volume":"38","author":"Primerano","year":"2014","journal-title":"J. Anal. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Yang, H.C., Chu, S.K., Huang, C.L., Kuo, H.W., Wang, S.C., Liu, S.W., Ho, I.-K., and Liu, Y.-L. (2016). Genome-Wide Pharmacogenomic Study on Methadone Maintenance Treatment Identifies SNP rs17180299 and Multiple Haplotypes on CYP2B6, SPON1, and GSG1L Associated with Plasma Concentrations of Methadone R- and S-enantiomers in Heroin-Dependent Patients. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1005910"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.bja.2019.08.010","article-title":"The anaesthetist, opioid analgesic drugs, and serotonin toxicity: A mechanistic and clinical review","volume":"124","author":"Baldo","year":"2020","journal-title":"Br. J. Anaesth."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"41","DOI":"10.18773\/austprescr.2021.004","article-title":"Opioids and antidepressants: Which combinations to avoid","volume":"44","author":"Perananthan","year":"2021","journal-title":"Aust. Prescr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1080\/00952990.2017.1420795","article-title":"Pharmacogenetic analysis of opioid dependence treatment dose and dropout rate","volume":"44","author":"Crist","year":"2018","journal-title":"Am. J. Drug Alcohol Abus."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1146\/annurev.pharmtox.010909.105826","article-title":"Pharmacogenetics of Drug Dependence: Role of Gene Variations in Susceptibility and Treatment","volume":"50","author":"Khokhar","year":"2010","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_37","unstructured":"(2025, February 07). Ficha T\u00e9cnica Eptadone 100 mg Soluci\u00f3n Oral. Agencia Espa\u00f1ola de Medicamentos y Productos Sanitarios. Available online: https:\/\/cima.aemps.es\/cima\/pdfs\/es\/ft\/69909\/fichatecnica_69909.html.pdf."},{"key":"ref_38","unstructured":"PRISMA Statement (2025, February 07). PRISMA Statement. Available online: https:\/\/www.prisma-statement.org."},{"key":"ref_39","unstructured":"(2025, February 07). Study Quality Assessment Tools|NHLBI, NIH, Available online: https:\/\/www.nhlbi.nih.gov\/health-topics\/study-quality-assessment-tools."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1097\/00004714-200104000-00016","article-title":"Cytochrome P450 2D6 genotype and methadone steady-state concentrations","volume":"21","author":"Eap","year":"2001","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.clpt.2005.08.011","article-title":"Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment","volume":"78","author":"Crettol","year":"2005","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.clpt.2005.09.010","article-title":"Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action","volume":"79","author":"Skarke","year":"2006","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.clpt.2006.09.012","article-title":"ABCB1 and cytochrome P450 genotypes and phenotypes: Influence on methadone plasma levels and response to treatment","volume":"80","author":"Crettol","year":"2006","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/sj.clpt.6100120","article-title":"Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers","volume":"81","author":"Eap","year":"2007","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.drugalcdep.2006.12.018","article-title":"Association of CYP2D6 ultrarapid metabolizer genotype with deficient patient satisfaction regarding methadone maintenance treatment","volume":"89","author":"Trujols","year":"2007","journal-title":"Drug Alcohol Depend."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1111\/j.1369-1600.2010.00274.x","article-title":"CYP2B6 and OPRM1 gene variations predict methadone-related deaths","volume":"16","author":"Bunten","year":"2011","journal-title":"Addict. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Fonseca, F., de la Torre, R.L., Pastor, A., Cuy\u00e0s, E., Pizarro, N., Khymenets, O., Farr\u00e9, M., and Torrens, M. (2011). Contribution of cytochrome P450 and ABCB1 genetic variability on methadone pharmacokinetics, dose requirements, and response. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019527"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1097\/FPC.0b013e32835cb2e2","article-title":"Contribution of CYP2B6 alleles in explaining extreme (S)-methadone plasma levels: A CYP2B6 gene resequencing study","volume":"23","author":"Dobrinas","year":"2013","journal-title":"Pharmacogenetics Genom."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1111\/bcp.12576","article-title":"Methadone dose in heroin-dependent patients: Role of clinical factors, comedications, genetic polymorphisms and enzyme activity","volume":"79","author":"Mouly","year":"2015","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s40291-015-0137-4","article-title":"A Possible Mechanistic Link Between the CYP2C19 Genotype, the Methadone Metabolite Ethylidene-1,5-Dimethyl-3,3-Diphenylpyrrolidene (EDDP), and Methadone-Induced Corrected QT Interval Prolongation in a Pilot Study","volume":"19","author":"Carlquist","year":"2015","journal-title":"Mol. Diagn. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1111\/bcpt.12602","article-title":"The ABCB1, rs9282564, AG and TT Genotypes and the COMT, rs4680, AA Genotype are Less Frequent in Deceased Patients with Opioid Addiction than in Living Patients with Opioid Addiction","volume":"119","author":"Christoffersen","year":"2016","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1093\/jat\/bkw135","article-title":"Tell-Tale SNPs: The Role of CYP2B6 in Methadone Fatalities","volume":"41","author":"Ahmad","year":"2017","journal-title":"J. Anal. Toxicol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s00414-021-02502-5","article-title":"Brain\/blood ratios of methadone and ABCB1 polymorphisms in methadone-related deaths","volume":"135","author":"Plattner","year":"2021","journal-title":"Int. J. Leg. Med."},{"key":"ref_54","unstructured":"PubChem (2025, February 07). CYP2B6\u2014Cytochrome P450 Family 2 Subfamily B Member 6 (Human), Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/gene\/CYP2B6\/human."},{"key":"ref_55","unstructured":"(2025, February 07). PharmVar. Available online: https:\/\/www.pharmvar.org\/gene\/CYP2B6."},{"key":"ref_56","unstructured":"(2025, February 07). ABCB1 ATP Binding Cassette Subfamily B Member 1 [Homo Sapiens (Human)]\u2014Gene\u2014NCBI, Available online: https:\/\/www.ncbi.nlm.nih.gov\/gene\/5243."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1002\/cpt.1643","article-title":"PharmVar GeneReview: CYP2D6","volume":"107","author":"Nofziger","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_58","unstructured":"(2025, February 07). CYP2D6 Cytochrome P450 Family 2 Subfamily D Member 6 (Gene\/Pseudogene) [Homo Sapiens (Human)]\u2014Gene\u2014NCBI, Available online: https:\/\/www.ncbi.nlm.nih.gov\/gene\/1565."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1097\/ALN.0000000000000867","article-title":"Methadone pharmacogenetics: CYP2B6 polymorphisms determine plasma concentrations, clearance and metabolism","volume":"123","author":"Kharasch","year":"2015","journal-title":"Anesthesiology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1097\/FTD.0000000000000437","article-title":"Combined Effect of CYP2B6 Genotype and Other Candidate Genes on a Steady-State Serum Concentration of Methadone in Opioid Maintenance Treatment","volume":"39","author":"Kringen","year":"2017","journal-title":"Ther. Drug Monit."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1002\/cpt.2166","article-title":"PharmVar GeneFocus: CYP2B6","volume":"110","author":"Desta","year":"2021","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1002\/cpt.3338","article-title":"Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2B6 Genotype and Methadone Therapy","volume":"116","author":"Robinson","year":"2024","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_63","unstructured":"PharmGKB (2025, February 07). Gene-Specific Information Tables for CYP2B6. Available online: https:\/\/www.pharmgkb.org\/page\/cyp2b6RefMaterials."},{"key":"ref_64","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_65","doi-asserted-by":"crossref","unstructured":"Mang\u00f3, K., Kiss, \u00c1.F., Fekete, F., Erd\u0151s, R., and Monostory, K. (2022). CYP2B6 allelic variants and non-genetic factors influence CYP2B6 enzyme function. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-07022-9"},{"key":"ref_66","first-page":"167","article-title":"The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part II: Pharmacological issues and further understanding","volume":"8","year":"2015","journal-title":"Rev. Psiquiatr. Salud Ment."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.lfs.2010.09.016","article-title":"Drug interactions associated with methadone, buprenorphine, cocaine, and HIV medications: Implications for pregnant women","volume":"88","year":"2011","journal-title":"Life Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/j.1521-0391.2009.00005.x","article-title":"Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: A review","volume":"19","author":"Sullivan","year":"2010","journal-title":"Am. J. Addict."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1097\/00004714-200204000-00017","article-title":"Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers","volume":"22","author":"Ladewig","year":"2002","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1097\/JCP.0b013e3180592ad2","article-title":"Increased (R)-methadone plasma concentrations by quetiapine in cytochrome P450s and ABCB1 genotyped patients","volume":"27","author":"Uehlinger","year":"2007","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1080\/10550490050172236","article-title":"The effect of sertraline on methadone plasma levels in methadone-maintenance patients","volume":"9","author":"Hamilton","year":"2000","journal-title":"Am. J. Addict."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e142","DOI":"10.1016\/j.jpainsymman.2021.08.007","article-title":"Pharmacogenetics of Methadone for Pain Management in Palliative Care","volume":"63","author":"Irwin","year":"2022","journal-title":"J. Pain Symptom Manag."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1093\/jbcr\/irac062","article-title":"Pharmacogenetic Gene-Drug Associations in Pediatric Burn and Surgery Patients","volume":"43","author":"Grimsrud","year":"2022","journal-title":"J. Burn. Care Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/cpt.2350","article-title":"An Evidence-Based Framework for Evaluating Pharmacogenomics Knowledge for Personalized Medicine","volume":"110","author":"Huddart","year":"2021","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1002\/jcph.1","article-title":"Role of cytochrome P4502B6 in methadone metabolism and clearance","volume":"53","author":"Kharasch","year":"2013","journal-title":"J. Clin. Pharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1097\/FPC.0b013e32833225e7","article-title":"The P450 oxidoreductase genotype is associated with CYP3A activity in vivo as measured by the midazolam phenotyping test","volume":"19","author":"Oneda","year":"2009","journal-title":"Pharmacogenetics Genom."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Rojas Velazquez, M.N., Therkelsen, S., and Pandey, A.V. (2023). Exploring Novel Variants of the Cytochrome P450 Reductase Gene (POR) from the Genome Aggregation Database by Integrating Bioinformatic Tools and Functional Assays. Biomolecules, 13.","DOI":"10.20944\/preprints202311.0653.v1"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"4881","DOI":"10.1111\/bcp.15393","article-title":"Methadone pharmacogenetics in vitro and in vivo: Metabolism by CYP2B6 polymorphic variants and genetic variability in paediatric disposition","volume":"88","author":"Wang","year":"2022","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1111\/j.1369-1600.2011.00349.x","article-title":"CYP2B6 SNPs are associated with methadone dose required for effective treatment of opioid addiction","volume":"18","author":"Levran","year":"2013","journal-title":"Addict. Biology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.jpainsymman.2023.09.017","article-title":"Comparison of the Effects of OPRM1 A118G Polymorphism Using Different Opioids: A Prospective Study","volume":"67","author":"Takemura","year":"2024","journal-title":"J. Pain Symptom Manag."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3552","DOI":"10.1111\/jcmm.13266","article-title":"Reduced dosing and liability in methadone maintenance treatment by targeting oestrogen signal for morphine addiction","volume":"21","author":"Chiang","year":"2017","journal-title":"J. Cell. Mol. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1111\/ajad.12921","article-title":"Review: Sex-based Differences in Treatment Outcomes for Persons with Opioid Use Disorder","volume":"28","author":"Huhn","year":"2019","journal-title":"Am. J. Addict."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/5\/623\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:21:32Z","timestamp":1760030492000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/5\/623"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,25]]},"references-count":82,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ph18050623"],"URL":"https:\/\/doi.org\/10.3390\/ph18050623","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,25]]}}}