Prediction of cytochromes P450 3A and 2C19 modulation by both inflammation and drug interactions using physiologically based pharmacokinetics

Article Article scientifique Article Prediction of cytochromes P450 3A and 2C19 modulation by both inflammation and drug interactions using physiologically based pharmacokinetics eng 2021-11-17 2022-01 author Lenoir Camille 0000-0001-6506-8629 777980 author Niederer Amine 777985 author Rollason Victoria 40955 author Desmeules Jules Alexandre 73542 author Daali Youssef 46042 author Samer Caroline Flora 105661 30-43 10.1002/psp4.12730 34791831 2163-8306 PMC8752107 https://ascpt.onlinelibrary.wiley.com/doi/10.1002/psp4.12730 Xenobiotics can interact with cytochromes P450 (CYPs), resulting in drug-drug interactions, but CYPs can also contribute to drug-disease interactions, especially in the case of inflammation, which downregulates CYP activities through pretranscriptional and posttranscriptional mechanisms. Interleukin-6 (IL-6), a key proinflammatory cytokine, is mainly responsible for this effect. The aim of our study was to develop a physiologically based pharmacokinetic (PBPK) model to foresee the impact of elevated IL-6 levels in combination with drug interactions with esomeprazole on CYP3A and CYP2C19. Data from a cohort of elective hip surgery patients whose CYP3A and CYP2C19 activities were measured before and after surgery were used to validate the accurate prediction of the developed models. Successive steps were to fit models for IL-6, esomeprazole, and omeprazole and its metabolite from the literature and to validate them. The models for midazolam and its metabolite were obtained from the literature. When appropriate, a correction factor was applied to convert drug concentrations from whole blood to plasma. Mean ratios between simulated and observed areas under the curve for omeprazole/5-hydroxy omeprazole, esomeprazole, and IL-6 were 1.53, 1.06, and 0.69, respectively, indicating an accurate prediction of the developed models. The impact of IL-6 and esomeprazole on the exposure to CYP3A and CYP2C19 probe substrates and respective metabolites were correctly predicted. Indeed, the ratio between predicted and observed mean concentrations were <2 for all observations (ranging from 0.51 to 1.7). The impact of IL-6 and esomeprazole on CYP3A and CYP2C19 activities after a hip surgery were correctly predicted with the developed PBPK models. Cytochrome P-450 CYP2C19 / drug effects Cytochrome P-450 CYP2C19 Inhibitors / pharmacology Cytochrome P-450 CYP3A / drug effects Cytochrome P-450 CYP3A Inhibitors / pharmacology Down-Regulation Drug Interactions Esomeprazole / pharmacology Humans Inflammation / physiopathology Interleukin-6 / blood Midazolam / pharmacokinetics Omeprazole / pharmacology Dewey 615 Dewey 617 63 Département d'anesthésiologie, pharmacologie, soins intensifs et urgences 229 31 Section des sciences pharmaceutiques 17 false 302 Groupe Desmeules Jules (pharmacologie/toxicologie) 567 1280 Pharmaco-omiques et médecine de précision 1003 CPT: pharmacometrics & systems pharmacology 11 1 e9714745-98bf-403a-8e60-ff1deefc0532 Article (Published version) Public Article-scientifique-from-europePmc.pdf 621573 application/pdf CC BY-NC-ND-4.0 4df741a5-bb95-4e47-99cf-298b01898862 Appendix Public PSP4-11-30-s008.docx 17169 application/vnd.openxmlformats-officedocument.wordprocessingml.document Table S1 49a285fb-44de-4c82-b5a8-cdf8b093c3e0 Appendix Public PSP4-11-30-s005.docx 15355 application/vnd.openxmlformats-officedocument.wordprocessingml.document Table S2 76d8dd43-5c59-4a8a-9560-489614bc120f Appendix Public PSP4-11-30-s006.pdf 550116 application/pdf Fig S1 8b6d1afd-6634-4428-aec5-a50bb3a0678d Appendix Public PSP4-11-30-s004.pdf 445626 application/pdf Fig S2 71f8c575-bc52-44d6-8a05-29a28de8f585 Appendix Public psp412730-sup-0005-modelfiles1.xml 518482 application/xml ModelFile S1 d45bd615-154c-42ed-aa7b-417ce63e011c Appendix Public psp412730-sup-0006-modelfiles2.xml 516873 application/xml ModelFile S2 28d991c7-6101-47c2-a403-b9f9b585f03f Appendix Public psp412730-sup-0007-modelfiles3.xml 515982 application/xml ModelFile S3 cdb9f0c8-1043-4295-8805-95224fecb5d4 Appendix Public psp412730-sup-0008-modelfiles4.xml 518898 application/xml ModelFile S4 openAccess Faculté de médecine / Section de médecine clinique / Département d'anesthésiologie, pharmacologie, soins intensifs et urgences Faculté des sciences / Section des sciences pharmaceutiques

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Prediction of cytochromes P450 3A and 2C19 modulation by both inflammation and drug interactions using physiologically based pharmacokinetics	CPT: pharmacometrics & systems pharmacology			2022	215	289

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