Physiologically based pharmacokinetic modeling of imatinib and N ‐desmethyl imatinib for drug–drug interaction predictions
AbstractThe first-generation tyrosine kinase inhibitor imatinib has revolutionized the development of targeted cancer therapy and remains among the frontline treatments, for example, against chronic myeloid leukemia. As a substrate of cytochrome P450 (CYP) 2C8, CYP3A4, and various transporters, imatinib is highly susceptible to drug –drug interactions (DDIs) when co-administered with corresponding perpetrator drugs. Additionally, imatinib and its main metaboliteN-desmethyl imatinib (NDMI) act as inhibitors of CYP2C8, CYP2D6, and CYP3A4 affecting their own metabolism as well as the exposure of co-medications. This work pr...
Source: CPT: Pharmacometrics and Systems Pharmacology - March 14, 2024 Category: Drugs & Pharmacology Authors: Helena Leonie Hanae Loer,
Christina Kovar,
Simeon R üdesheim,
Fatima Zahra Marok,
Laura Maria Fuhr,
Dominik Selzer,
Matthias Schwab,
Thorsten Lehr Tags: ARTICLE Source Type: research
Mechanistic Determinants of Daprodustat Drug-Drug Interactions and Pharmacokinetics in Hepatic Dysfunction and Chronic Kidney Disease: Significance of OATP1B-CYP2C8 Interplay
Clin Pharmacol Ther. 2024 Feb 26. doi: 10.1002/cpt.3215. Online ahead of print.ABSTRACTDaprodustat is the first oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved recently for the treatment of anemia caused by chronic kidney disease (CKD) in adults receiving dialysis. We evaluated the role of organic anion transporting polypeptide (OATP)1B-mediated hepatic uptake transport in the pharmacokinetics (PKs) of daprodustat using in vitro and in vivo studies, and physiologically-based PK (PBPK) modeling of its drug-drug interactions (DDIs) with inhibitor drugs. In vitro, daprodustat showed specific transport by O...
Source: Clinical Pharmacology and Therapeutics - February 26, 2024 Category: Drugs & Pharmacology Authors: Yi-An Bi Samantha Jordan Amanda King-Ahmad Mark A West Manthena V S Varma Source Type: research
Mechanistic Determinants of Daprodustat Drug-Drug Interactions and Pharmacokinetics in Hepatic Dysfunction and Chronic Kidney Disease: Significance of OATP1B-CYP2C8 Interplay
Clin Pharmacol Ther. 2024 Feb 26. doi: 10.1002/cpt.3215. Online ahead of print.ABSTRACTDaprodustat is the first oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved recently for the treatment of anemia caused by chronic kidney disease (CKD) in adults receiving dialysis. We evaluated the role of organic anion transporting polypeptide (OATP)1B-mediated hepatic uptake transport in the pharmacokinetics (PKs) of daprodustat using in vitro and in vivo studies, and physiologically-based PK (PBPK) modeling of its drug-drug interactions (DDIs) with inhibitor drugs. In vitro, daprodustat showed specific transport by O...
Source: Clinical Pharmacology and Therapeutics - February 26, 2024 Category: Drugs & Pharmacology Authors: Yi-An Bi Samantha Jordan Amanda King-Ahmad Mark A West Manthena V S Varma Source Type: research
Inhibition of tumor migration and invasion by fenofibrate via suppressing epithelial-mesenchymal transition in breast cancers
In this study, we examined five lipid-lowering drugs: swertiamarin, gemfibrozil, clofibrate, bezafibrate, and fenofibrate in triple-negative breast cancer, which is the most migration-prone subtype. Using human and murine triple-negative breast cancer cell lines (Hs 578 t and 4 T1), we found that fenofibrate displays the highest potential in inhibiting the colony formation, wound healing, and transwell migration. We further discovered that fenofibrate reduces the activity of pro-metastatic enzymes, matrix metalloproteinases (MMP)-9 and MMP-2. In addition, epithelial markers including E-cadherin and Zonula occludens-1 are i...
Source: Toxicology and Applied Pharmacology - January 12, 2024 Category: Toxicology Authors: Yen-Chang Chen Jia-Hong Chen Cheng-Fang Tsai Chen-Teng Wu Pei-Chun Chang Wei-Lan Yeh Source Type: research
A computational approach to analyzing the functional and structural impacts of Tripeptidyl-Peptidase 1 missense mutations in neuronal ceroid lipofuscinosis
In this study, we retrieved a mutational dataset screening for TPP1 protein from various databases (ClinVar, UniProt, HGMD). Fifty-six missense mutants were enumerated with computational methods to perceive the significant mutants (G475R and G501C) and correlated with clinical and literature data. A structure-based screening method was initiated to understand protein-ligand interaction and dynamic simulation. The docking procedure was performed for the native (3EDY) and mutant (G473R and G501C) structures with Gemfibrozil (gem), which lowers the lipid level, decreases the triglycerides amount in the blood circulation, and ...
Source: Metabolic Brain Disease - January 8, 2024 Category: Neurology Source Type: research
Risk factors for anticoagulant-associated gastrointestinal hemorrhage: a systematic review and meta-analysis
CONCLUSIONS: The study found that anemia, co-administration of gemfibrozil, co-administration of verapamil or diltiazem, INR, heart failure, myocardial infarction et al. were associated with anticoagulation-related GIB, and these factors were not in the existing prediction models. This study informs risk prediction for anticoagulant-associated GIB, it also informs guidelines for GIB prevention and future research.PMID:38062723 | DOI:10.3904/kjim.2023.098 (Source: The Korean Journal of Internal Medicine)
Source: The Korean Journal of Internal Medicine - December 8, 2023 Category: Internal Medicine Authors: Fuxin Ma Shuyi Wu Shiqi Li Zhiwei Zeng Jinhua Zhang Source Type: research
Risk factors for anticoagulant-associated gastrointestinal hemorrhage: a systematic review and meta-analysis
CONCLUSIONS: The study found that anemia, co-administration of gemfibrozil, co-administration of verapamil or diltiazem, INR, heart failure, myocardial infarction et al. were associated with anticoagulation-related GIB, and these factors were not in the existing prediction models. This study informs risk prediction for anticoagulant-associated GIB, it also informs guidelines for GIB prevention and future research.PMID:38062723 | DOI:10.3904/kjim.2023.098 (Source: The Korean Journal of Internal Medicine)
Source: The Korean Journal of Internal Medicine - December 8, 2023 Category: Internal Medicine Authors: Fuxin Ma Shuyi Wu Shiqi Li Zhiwei Zeng Jinhua Zhang Source Type: research
Risk factors for anticoagulant-associated gastrointestinal hemorrhage: a systematic review and meta-analysis
CONCLUSIONS: The study found that anemia, co-administration of gemfibrozil, co-administration of verapamil or diltiazem, INR, heart failure, myocardial infarction et al. were associated with anticoagulation-related GIB, and these factors were not in the existing prediction models. This study informs risk prediction for anticoagulant-associated GIB, it also informs guidelines for GIB prevention and future research.PMID:38062723 | DOI:10.3904/kjim.2023.098 (Source: The Korean Journal of Internal Medicine)
Source: The Korean Journal of Internal Medicine - December 8, 2023 Category: Internal Medicine Authors: Fuxin Ma Shuyi Wu Shiqi Li Zhiwei Zeng Jinhua Zhang Source Type: research
Risk factors for anticoagulant-associated gastrointestinal hemorrhage: a systematic review and meta-analysis
CONCLUSIONS: The study found that anemia, co-administration of gemfibrozil, co-administration of verapamil or diltiazem, INR, heart failure, myocardial infarction et al. were associated with anticoagulation-related GIB, and these factors were not in the existing prediction models. This study informs risk prediction for anticoagulant-associated GIB, it also informs guidelines for GIB prevention and future research.PMID:38062723 | DOI:10.3904/kjim.2023.098 (Source: The Korean Journal of Internal Medicine)
Source: The Korean Journal of Internal Medicine - December 8, 2023 Category: Internal Medicine Authors: Fuxin Ma Shuyi Wu Shiqi Li Zhiwei Zeng Jinhua Zhang Source Type: research
Are 20-hydroxyecdysone and related genes potential biomarkers of sublethal exposure to lipid-altering contaminants?
Environ Sci Pollut Res Int. 2023 Nov 27. doi: 10.1007/s11356-023-31087-2. Online ahead of print.ABSTRACTIn Daphnia magna, 20-hydroecdysone (20E) is the main molting hormone and its metabolism is of interest to identify new biomarkers of exposure to contaminants. The present study aimed to (i) assess baseline levels of 20E and transcription levels of four related-genes (shade, neverland, ultraspiracle, and ecdysteroid receptor); and (ii) evaluate effects in D. magna after 21 days of exposure to fenarimol (anti-ecdysteroid) and a mixture of gemfibrozil and clofibric acid (lipid-lowering drugs) at sublethal concentrations. En...
Source: Environmental Science and Pollution Research International - November 27, 2023 Category: Environmental Health Authors: Hugo Alarie Nadia C ôté Luc Gaudreau Magali Houde Pedro A Segura Source Type: research
Creation of novel sensitive probe substrate and moderate inhibitor models for a comprehensive prediction of CYP2C8 interactions for tucatinib
Clin Pharmacol Ther. 2023 Nov 16. doi: 10.1002/cpt.3104. Online ahead of print.ABSTRACTA physiologically based pharmacokinetic (PBPK) model was developed to simulate plasma concentrations of tucatinib (Tukysa®) after single-dose or multiple-dose administration of 300 mg BID orally. This PBPK model was subsequently applied to support evaluation of DDI risk as a perpetrator resulting from tucatinib inhibition of CYP3A4, CYP2C8, CYP2C9, P-gp, or MATE1/2-K. The PBPK model was also applied to support evaluation of DDI risk as a victim resulting from co-administration with CYP3A4 or CYP2C8 inhibitors, or a CYP3A4 inducer. After...
Source: Clinical Pharmacology and Therapeutics - November 16, 2023 Category: Drugs & Pharmacology Authors: Ian E Templeton Karen Rowland-Yeo Hannah M Jones Christopher J Endres Ariel R Topletz-Erickson Hao Sun Anthony J Lee Source Type: research
Interplay of UDP-Glucuronosyltransferase and CYP2C8 for CYP2C8 Mediated Drug Oxidation and Its Impact on Drug –Drug Interaction Produced by Standardized CYP2C8 Inhibitors, Clopidogrel and Gemfibrozil
ConclusionThese findings substantially enhance our comprehension of CYP2C8-mediated oxidation and DDIs, holding crucial implications for drug development and the planning of clinical trials involving these inhibitors. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - November 3, 2023 Category: Drugs & Pharmacology Source Type: research
