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Physiologically-based pharmacokinetic modeling of quinidine to establish a CYP3A4, P-gp, and CYP2D6 drug-drug-gene interaction network.
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- معلومة اضافية
- المصدر:
Publisher: Wiley Country of Publication: United States NLM ID: 101580011 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2163-8306 (Electronic) Linking ISSN: 21638306 NLM ISO Abbreviation: CPT Pharmacometrics Syst Pharmacol Subsets: MEDLINE
- بيانات النشر:
Publication: 2015- : Hoboken, NJ : Wiley
Original Publication: New York, NY : Nature Pub. Group
- الموضوع:
- نبذة مختصرة :
The antiarrhythmic agent quinidine is a potent inhibitor of cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) and is therefore recommended for use in clinical drug-drug interaction (DDI) studies. However, as quinidine is also a substrate of CYP3A4 and P-gp, it is susceptible to DDIs involving these proteins. Physiologically-based pharmacokinetic (PBPK) modeling can help to mechanistically assess the absorption, distribution, metabolism, and excretion processes of a drug and has proven its usefulness in predicting even complex interaction scenarios. The objectives of the presented work were to develop a PBPK model of quinidine and to integrate the model into a comprehensive drug-drug(-gene) interaction (DD(G)I) network with a diverse set of CYP3A4 and P-gp perpetrators as well as CYP2D6 and P-gp victims. The quinidine parent-metabolite model including 3-hydroxyquinidine was developed using pharmacokinetic profiles from clinical studies after intravenous and oral administration covering a broad dosing range (0.1-600 mg). The model covers efflux transport via P-gp and metabolic transformation to either 3-hydroxyquinidine or unspecified metabolites via CYP3A4. The 3-hydroxyquinidine model includes further metabolism by CYP3A4 as well as an unspecific hepatic clearance. Model performance was assessed graphically and quantitatively with greater than 90% of predicted pharmacokinetic parameters within two-fold of corresponding observed values. The model was successfully used to simulate various DD(G)I scenarios with greater than 90% of predicted DD(G)I pharmacokinetic parameter ratios within two-fold prediction success limits. The presented network will be provided to the research community and can be extended to include further perpetrators, victims, and targets, to support investigations of DD(G)Is.
(© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- الرقم المعرف:
EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
EC 1.14.14.1 (Cytochrome P-450 CYP3A)
ITX08688JL (Quinidine)
0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
0 (Cytochrome P-450 CYP3A Inhibitors)
EC 1.14.14.55 (CYP3A4 protein, human)
- الموضوع:
Date Created: 20230511 Date Completed: 20230817 Latest Revision: 20230818
- الموضوع:
20240829
- الرقم المعرف:
PMC10431052
- الرقم المعرف:
10.1002/psp4.12981
- الرقم المعرف:
37165978
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