ArticleBritish journal of clinical pharmacology2022
Proteomics of colorectal cancer liver metastasis: A quantitative focus on drug elimination and pharmacodynamics effects.
Article in British journal of clinical pharmacology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Article
- In vivo Pharmacokinetic Interactions Between Palbociclib and Rivaroxaban or Apixaban: Implications for Increased Drug Exposure and Dose Adjustments.Drug design, development and therapy · 2025Article
- Decoding Drug Interactions: Character and Degree of Pharmacokinetic Interactions Between Telmisartan and Sorafenib or Donafenib in Rats.Drug design, development and therapy · 2025Article
- Personalized Medicine Approach to Proteomics and Metabolomics of Cytochrome P450 Enzymes: A Narrative Review.European journal of drug metabolism and pharmacokinetics · 2024Review
- Membrane transporters in drug development and as determinants of precision medicine.Nature reviews. Drug discovery · 2024Review
- The Role of CYPs and Transporters in the Biotransformation and Transport of the Anti-hepatitis C Antiviral Agents Asunaprevir, Daclatasvir, and Beclabuvir: Impact of Liver Disease, Race and Drug-drug Interactions on Safety and Efficacy.Current drug metabolism · 2024Review
- Utility of Physiologically Based Pharmacokinetic Modeling to Investigate the Impact of Physiological Changes of Pregnancy and Cancer on Oncology Drug Pharmacokinetics.Pharmaceutics · 2023Article
- Article
- Protein Abundance of Drug Metabolizing Enzymes in Human Hepatitis C Livers.International journal of molecular sciences · 2023Article
- Proteomic quantification of receptor tyrosine kinases involved in the development and progression of colorectal cancer liver metastasis.Frontiers in oncology · 2023Article
- Quantitative Proteomics of Hepatic Drug-Metabolizing Enzymes and Transporters in Patients With Colorectal Cancer Metastasis.Clinical pharmacology and therapeutics · 2022Article
- Sorafenib Chemosensitization by Caryophyllane Sesquiterpenes in Liver, Biliary, and Pancreatic Cancer Cells: The Role of STAT3/ABC Transporter Axis.Pharmaceutics · 2022Article
- Proteomics of colorectal cancer liver metastasis: A quantitative focus on drug elimination and pharmacodynamics effects.British journal of clinical pharmacology · 2022Article
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsThis study aims to quantify drug-metabolising enzymes, transporters, receptor tyrosine kinases (RTKs) and protein markers (involved in pathways affected in cancer) in pooled healthy, histologically normal and matched cancerous liver microsomes from colorectal cancer liver metastasis (CRLM) patients.
methodsMicrosomal fractionation was performed and pooled microsomes were prepared. Global and accurate mass and retention time liquid chromatography-mass spectrometry proteomics were used to quantify proteins. A QconCAT (KinCAT) for the quantification of RTKs was designed and applied for the first time. Physiologically based pharmacokinetic (PBPK) simulations were performed to assess the contribution of altered abundance of drug-metabolising enzymes and transporters to changes in pharmacokinetics.
resultsMost CYPs and UGTs were downregulated in histologically normal relative to healthy samples, and were further reduced in cancer samples (up to 54-fold). The transporters, MRP2/3, OAT2/7 and OATP2B1/1B3/1B1 were downregulated in CRLM. Application of abundance data in PBPK models for substrates with different attributes indicated substantially lower (up to 13-fold) drug clearance when using cancer-specific instead of default parameters in cancer population. Liver function markers were downregulated, while inflammation proteins were upregulated (by up to 76-fold) in cancer samples. Various pharmacodynamics markers (e.g. RTKs) were altered in CRLM. Using global proteomics, we examined proteins in pathways relevant to cancer (such as metastasis and desmoplasia), including caveolins and collagen chains, and confirmed general over-expression of such pathways.
conclusionThis study highlights impaired drug metabolism, perturbed drug transport and altered abundance of cancer markers in CRLM, demonstrating the importance of population-specific abundance data in PBPK models for cancer.
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