دورية أكاديمية
Mechanistic Account of Distinct Change in Organic Anion Transporting Polypeptide 1B (OATP1B) Substrate Pharmacokinetics during OATP1B-Mediated Drug-Drug Interactions Using Physiologically Based Pharmacokinetic Modeling.
| العنوان: | Mechanistic Account of Distinct Change in Organic Anion Transporting Polypeptide 1B (OATP1B) Substrate Pharmacokinetics during OATP1B-Mediated Drug-Drug Interactions Using Physiologically Based Pharmacokinetic Modeling. |
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| المؤلفون: | Hegde PV; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana., Morse BL; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana bridget_morse@lilly.com. |
| المصدر: | Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2024 Jul 16; Vol. 52 (8), pp. 886-898. Date of Electronic Publication: 2024 Jul 16. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics, etc.] Country of Publication: United States NLM ID: 9421550 Publication Model: Electronic Cited Medium: Internet ISSN: 1521-009X (Electronic) Linking ISSN: 00909556 NLM ISO Abbreviation: Drug Metab Dispos Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Bethesda, Md., etc., American Society for Pharmacology and Experimental Therapeutics, etc.] |
| مواضيع طبية MeSH: | Drug Interactions*/physiology , Liver-Specific Organic Anion Transporter 1*/metabolism , Liver-Specific Organic Anion Transporter 1*/genetics , Rifampin*/pharmacokinetics , Rifampin*/pharmacology , Models, Biological*, Humans ; Cytochrome P-450 CYP3A/metabolism ; Half-Life ; Liver/metabolism ; Cytochrome P-450 CYP3A Inducers/pharmacokinetics ; Cytochrome P-450 CYP3A Inducers/pharmacology ; Quinolines |
| مستخلص: | The role of transporters in drug clearance is widely acknowledged, directly and indirectly by facilitating tissue/enzyme exposure. Through the latter, transporters also affect volume of distribution. Drug-drug interactions (DDIs) involving organic anion transporting polypeptides (OATPs) 1B1/1B3 and SLCO1B1 pharmacogenetics lead to altered pharmacokinetics of OATP1B substrates; however, several factors may confound direct interpretation of pharmacokinetic parameters from these clinical studies using noncompartmental analysis (NCA). A review of clinical data herein indicates a single dose of OATP1B inhibitor rifampin almost never leads to increased substrate half-life but often a decrease and that most clinical OATP1B substrates are CYP3A4 substrates and/or undergo enterohepatic cycling (EHC). Using hypothetically simple OATP1B substrate physiologically based pharmacokinetic (PBPK) models, simulated effect of rifampin differed from specific OATP1B inhibition due to short rifampin half-life causing dissipation of OATP1B inhibition over time combined with CYP3A4 induction. Calculated using simulated tissue data, volume of distribution indeed decreased with OATP1B inhibition and was expectedly limited to the contribution of liver volume. However, an apparent and counterintuitive effect of rifampin on volume greater than that on clearance resulted for CYP3A4 substrates using NCA. The effect of OATP1B inhibition and rifampin on OATP1B substrate models incorporating EHC plus or minus renal clearance was distinct compared with simpler models. Using PBPK models incorporating reversible lactone metabolism for clinical OATP1B substrates atorvastatin and pitavastatin, DDIs reporting decreased half-life with rifampin were reproduced. These simulations provide an explanation for the distinct change in OATP1B substrate pharmacokinetics observed in clinical studies, including changes in volume of distribution and additional mechanisms. SIGNIFICANCE STATEMENT: Transporters are involved in drug clearance and volume of distribution, and distinct changes in OATP1B substrate pharmacokinetics are observed with OATP1B inhibitor rifampin. Using hypothetical and validated PBPK models and simulations, this study addresses the limitations of single-dose rifampin and complicated clinical OATP1B substrate disposition in evaluating the pharmacokinetic parameters of OATP1B substrates during rifampin drug-drug interactions (DDIs). These models account for change in volume of distribution and identify additional mechanisms underlying apparent pharmacokinetic changes in OATP1B DDIs. (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.) |
| المشرفين على المادة: | 0 (Liver-Specific Organic Anion Transporter 1) VJT6J7R4TR (Rifampin) 0 (SLCO1B1 protein, human) EC 1.14.14.1 (Cytochrome P-450 CYP3A) M5681Q5F9P (pitavastatin) EC 1.14.14.55 (CYP3A4 protein, human) 0 (Cytochrome P-450 CYP3A Inducers) 0 (Quinolines) |
| تواريخ الأحداث: | Date Created: 20240513 Date Completed: 20240716 Latest Revision: 20240814 |
| رمز التحديث: | 20240814 |
| DOI: | 10.1124/dmd.124.001708 |
| PMID: | 38740464 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-009X |
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| DOI: | 10.1124/dmd.124.001708 |