{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T05:43:39Z","timestamp":1761198219322,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T00:00:00Z","timestamp":1684886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FCT and FEDER (European Union)","award":["IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["IF\/00092\/2014\/CP1255\/CT0004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Drug\u2013drug interactions (DDIs) represent a significant concern in healthcare, particularly for patients undergoing polytherapy. DDIs can lead to a range of outcomes, from decreased therapeutic effectiveness to adverse effects. Salbutamol, a bronchodilator recommended for the treatment of respiratory diseases, is metabolized by cytochrome P450 (CYP) enzymes, which can be inhibited or induced by co-administered drugs. Studying DDIs involving salbutamol is crucial for optimizing drug therapy and preventing adverse outcomes. Here, we aimed to investigate CYP-mediated DDIs between salbutamol and fluvoxamine through in silico approaches. The physiologically based pharmacokinetic (PBPK) model of salbutamol was developed and validated using available clinical PK data, whereas the PBPK model of fluvoxamine was previously verified by GastroPlus. Salbutamol\u2013fluvoxamine interaction was simulated according to different regimens and patient\u2019s characteristics (age and physiological status). The results demonstrated that co-administering salbutamol with fluvoxamine enhanced salbutamol exposure in certain situations, especially when fluvoxamine dosage increased. To sum up, this study demonstrated the utility of PBPK modeling in predicting CYP-mediated DDIs, making it a pioneer in PK DDI research. Furthermore, this study provided insights into the relevance of regular monitoring of patients taking multiple medications, regardless of their characteristics, to prevent adverse outcomes and for the optimization of the therapeutic regimen, in cases where the therapeutic benefit is no longer experienced.<\/jats:p>","DOI":"10.3390\/pharmaceutics15061586","type":"journal-article","created":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T01:36:28Z","timestamp":1684978588000},"page":"1586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Prediction of CYP-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Modeling: A Case Study of Salbutamol and Fluvoxamine"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7003-4957","authenticated-orcid":false,"given":"Lara","family":"Marques","sequence":"first","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, Al. Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, Al. Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Dr. Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1001\/jama.1997.03540410031017","article-title":"Adverse Drug Events in Hospitalized Patients-Reply","volume":"277","author":"Burke","year":"1997","journal-title":"JAMA J. Am. Med. Assoc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"814858","DOI":"10.3389\/fphar.2021.814858","article-title":"A Review of Approaches for Predicting Drug\u2013Drug Interactions Based on Machine Learning","volume":"12","author":"Han","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1067\/mem.2001.119456","article-title":"Polypharmacy, Adverse Drug-Related Events, and Potential Adverse Drug Interactions in Elderly Patients Presenting to an Emergency Department","volume":"38","author":"Hohl","year":"2001","journal-title":"Ann. Emerg. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"326","DOI":"10.4103\/0975-1483.66807","article-title":"Drug Interaction and Pharmacist","volume":"2","author":"Ansari","year":"2010","journal-title":"J. Young Pharm."},{"key":"ref_5","first-page":"123","article-title":"Mechanisms and the Clinical Relevance of Complex Drug\u2013Drug Interactions","volume":"10","author":"Roberts","year":"2018","journal-title":"Clin. Pharmacol. Adv. Appl."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Peng, Y., Cheng, Z., and Xie, F. (2021). Evaluation of Pharmacokinetic Drug-Drug Interactions: A Review of the Mechanisms, in Vitro and in Silico Approaches. Metabolites, 11.","DOI":"10.3390\/metabo11020075"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1002\/cpt.1434","article-title":"Pharmacodynamic Drug\u2013Drug Interactions","volume":"105","author":"Niu","year":"2019","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.cpem.2005.04.006","article-title":"Drug Interactions\u2014A Review","volume":"6","author":"Manzi","year":"2005","journal-title":"Clin. Pediatr. Emerg. Med."},{"key":"ref_9","first-page":"38","article-title":"Cytochrome P450 Structure, Function and Clinical Significance: A Review","volume":"19","author":"Manikandan","year":"2017","journal-title":"Curr. Drug Targets"},{"key":"ref_10","unstructured":"Rowland, M., and Tozer, T. (2005). Clinical Pharmacokinetics and Pharmacodynamics, Lippincott Williams & Wilkins."},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"2102730","DOI":"10.1183\/13993003.02730-2021","article-title":"Global Initiative for Asthma Strategy 2021: Executive Summary and Rationale for Key Changes","volume":"59","author":"Reddel","year":"2022","journal-title":"Eur. Respir. J."},{"key":"ref_13","unstructured":"(2023, March 09). 2022 GINA Main Report\u2014Global Initiative for Asthma\u2014GINA. Available online: https:\/\/ginasthma.org\/gina-reports\/."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1097\/ACI.0b013e32835c16b6","article-title":"Asthma and Comorbidities","volume":"13","author":"Ledford","year":"2013","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3200","DOI":"10.1002\/jssc.201900330","article-title":"Identification of the Major Metabolites of (R)-Salbutamol in Human Urine, Plasma and Feces Using Ultra High Performance Liquid Chromatography Coupled with Quadrupole Time-of-Flight Mass Spectrometry","volume":"42","author":"Ye","year":"2019","journal-title":"J. Sep. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1183\/09031936.99.13612369","article-title":"Stereoselective Pharmacokinetics of S-Salbutamol after Administration of the Racemate in Healthy Volunteers","volume":"13","author":"Schmekel","year":"1999","journal-title":"Eur. Respir. J."},{"key":"ref_17","first-page":"105","article-title":"Albuterol: An Adrenergic Agent for Use in the Treatment of Asthma Pharmacology, Pharmacokinetics and Clinical Use","volume":"4","author":"Ahrens","year":"1984","journal-title":"Pharmacol. Pharm."},{"key":"ref_18","unstructured":"(2023, January 14). Salbutamol: Uses, Interactions, Mechanism of Action DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB01001."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Marques, L., and Vale, N. (2023). Unraveling the Impact of Salbutamol Polytherapy: Clinically Relevant Drug Interactions. Futur. Pharmacol., 3.","DOI":"10.3390\/futurepharmacol3010019"},{"key":"ref_20","unstructured":"(2023, May 14). Albuterol\u2014Drug Usage Statistics, ClinCalc DrugStats Database. Available online: https:\/\/clincalc.com\/DrugStats\/Drugs\/Albuterol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"PkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures","volume":"58","author":"Pires","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_23","unstructured":"(2022, October 10). Salbutamol: Uses, Dosage, Side Effects, Warnings\u2014Drugs.Com. Available online: https:\/\/www.drugs.com\/salbutamol.html."},{"key":"ref_24","unstructured":"(2023, April 22). Salbutamol C13H21NO3\u2014PubChem, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Salbutamol."},{"key":"ref_25","unstructured":"(2023, April 22). COVID-19 Treatment Guidelines Panel Coronavirus Disease 2019 (COVID-19) Treatment Guidelines, Available online: https:\/\/www.covid19treatmentguidelines.nih.gov\/."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e42","DOI":"10.1016\/S2214-109X(21)00448-4","article-title":"Effect of Early Treatment with Fluvoxamine on Risk of Emergency Care and Hospitalisation among Patients with COVID-19: The TOGETHER Randomised, Platform Clinical Trial","volume":"10","author":"Reis","year":"2022","journal-title":"Lancet Glob. Heal."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e331","DOI":"10.1016\/S2214-109X(21)00592-1","article-title":"Fluvoxamine for the Treatment of COVID-19","volume":"10","author":"Marzolini","year":"2022","journal-title":"Lancet Glob. Health"},{"key":"ref_28","first-page":"CD015391","article-title":"Fluvoxamine for the Treatment of COVID-19","volume":"9","author":"Nyirenda","year":"2022","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S744","DOI":"10.1111\/j.1365-2125.2004.02282.x","article-title":"The Effect of Selective Serotonin Re-Uptake Inhibitors on Cytochrome P4502D6 (CYP2D6) Activity in Human Liver Microsomes","volume":"58","author":"Crewe","year":"2004","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_30","first-page":"231","article-title":"Drug Interactions and the Cytochrome P-450 System","volume":"53","author":"Menke","year":"2000","journal-title":"S. D. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2165\/00003088-199500291-00003","article-title":"Overview of the Pharmacokinetics of Fluvoxamine","volume":"29","year":"1995","journal-title":"Clin. Pharmacokinet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1016\/0006-2952(93)90272-X","article-title":"Fluvoxamine Is a Potent Inhibitor of Cytochrome P4501A2","volume":"45","author":"Brosen","year":"1993","journal-title":"Biochem. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1111\/j.1365-2125.1986.tb02939.x","article-title":"Pharmacokinetics of Intravenous and Oral Salbutamol and Its Sulphate Conjugate","volume":"22","author":"Morgan","year":"1986","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_34","unstructured":"(2023, April 22). Fluvoxamine: Uses, Interactions, Mechanism of Action DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB00176."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1111\/bcp.14094","article-title":"Prescribing Medicines to Older People\u2014How to Consider the Impact of Ageing on Human Organ and Body Functions","volume":"86","author":"Wilting","year":"2020","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"485","DOI":"10.2165\/00003088-198005060-00001","article-title":"Clinical Pharmacokinetics in Newborns and Infants: Age-Related Differences and Therapeutic Implications","volume":"5","author":"Morselli","year":"1980","journal-title":"Clin. Pharmacokinet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1002\/jppr.1373","article-title":"Pharmacokinetic Changes with Growth and Development between Birth and Adulthood","volume":"47","year":"2017","journal-title":"J. Pharm. Pract. Res."},{"key":"ref_38","first-page":"349","article-title":"Developmental Pharmacology\u2014Drug Disposition, Action, and Therapy in Infants and Children","volume":"12","author":"Kearns","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1046\/j.1528-1157.43.s.3.5.x","article-title":"Children versus Adults: Pharmacokinetic and Adverse-Effect Differences","volume":"43","author":"Anderson","year":"2002","journal-title":"Epilepsia"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.maturitas.2017.03.004","article-title":"Drug Metabolism in the Elderly: A Multifactorial Problem?","volume":"100","author":"Waring","year":"2017","journal-title":"Maturitas"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1111\/j.1365-2125.2004.02096.x","article-title":"Drug Metabolism and Ageing","volume":"57","author":"Kinirons","year":"2004","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/clpt.1990.164","article-title":"Effects of Age and Gender on in Vitro Properties of Human Liver Microsomal Monooxygenases","volume":"48","author":"Schmucker","year":"1990","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0009-9236(97)90166-1","article-title":"Age and Cytochrome P450-Linked Drug Metabolism in Humans: An Analysis of 226 Subjects with Equal Histopathologic Conditions","volume":"61","author":"Sotaniemi","year":"1997","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"144","DOI":"10.5507\/bp.2017.026","article-title":"Effects of Obesity on Liver Cytochromes P450 in Various Animal Models","volume":"161","author":"Tomankova","year":"2017","journal-title":"Biomed. Pap."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"277","DOI":"10.2165\/11599410-000000000-00000","article-title":"Impact of Obesity on Drug Metabolism and Elimination in Adults and Children","volume":"51","author":"Brill","year":"2012","journal-title":"Clin. Pharmacokinet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1007\/s43440-020-00127-w","article-title":"End-Stage Renal Disease Reduces the Expression of Drug-Metabolizing Cytochrome P450s","volume":"72","author":"Kiss","year":"2020","journal-title":"Pharmacol. Rep."},{"key":"ref_47","unstructured":"(2023, May 14). The First Trimester Johns Hopkins Medicine. Available online: https:\/\/www.hopkinsmedicine.org\/health\/wellness-and-prevention\/the-first-trimester."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1517\/17425251003677755","article-title":"Altered Drug Metabolism during Pregnancy: Hormonal Regulation of Drug-Metabolizing Enzymes","volume":"6","author":"Jeong","year":"2010","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_49","unstructured":"(2023, April 23). Fluvoxamine Use During Pregnancy Drugs.Com. Available online: https:\/\/www.drugs.com\/pregnancy\/fluvoxamine.html."},{"key":"ref_50","unstructured":"(2023, April 23). Salbutamol: Inhaler to Relieve Asthma and Breathlessness\u2014NHS. Available online: https:\/\/www.nhs.uk\/medicines\/salbutamol-inhaler\/."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"989","DOI":"10.2165\/00003088-200544100-00001","article-title":"Pregnancy-Induced Changes in Pharmacokinetics: A Mechanistic-Based Approach","volume":"44","author":"Anderson","year":"2005","journal-title":"Clin. Pharmacokinet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1146\/annurev.pharmtox.44.101802.121453","article-title":"Sex Differences in Pharmacokinetics and Pharmacodynamics","volume":"44","author":"Gandhi","year":"2004","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1124\/mol.109.056705","article-title":"Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes","volume":"76","author":"Waxman","year":"2009","journal-title":"Mol. Pharmacol."},{"key":"ref_54","unstructured":"(2023, April 23). Gender Differences in Pharmacokinetics. Available online: https:\/\/www.uspharmacist.com\/article\/gender-differences-in-pharmacokinetics."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"39","DOI":"10.31887\/DCNS.2004.6.1\/drubinow","article-title":"Sex-Dependent Modulation of Treatment Response","volume":"6","author":"Rubinow","year":"2004","journal-title":"Dialogues Clin. Neurosci."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/6\/1586\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:41:08Z","timestamp":1760125268000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/6\/1586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,24]]},"references-count":55,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["pharmaceutics15061586"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15061586","relation":{},"ISSN":["1999-4923"],"issn-type":[{"type":"electronic","value":"1999-4923"}],"subject":[],"published":{"date-parts":[[2023,5,24]]}}}