Establishing the capacity to monitor proteins relevant to the study of drug exposure and response using liver-derived extracellular vesicles

Research output: Contribution to journalArticlepeer-review

28 Downloads (Pure)

Abstract

Aims
Drug exposure and response is determined by pharmacokinetic (PK) and pharmacodynamic (PD) profiles. Interindividual differences in abundance of drug metabolizing enzymes (DMEs) and drug target proteins underpin PK and PD variability and impact treatment efficacy and tolerability. Extracellular vesicles (EVs) carry protein cargo inherited from originating cells and may be useful for defining differences in key proteins related to hepatic drug metabolism and the treatment of metabolic-associated fatty liver disease (MAFLD). We sought to quantify these proteins in liver-derived EVs and establish the profile relative to paired tissue.

Methods
EVs were recovered from human liver tissue samples (LT-EV, n = 11). Targeted liquid chromatography with tandem mass spectrometry (LC–MS/MS) assays were employed for absolute quantification of proteins in EV isolates and matched liver tissue.

Results
DMEs and MAFLD drug targets were readily detected and quantified in LT-EVs. Twelve of 15 DMEs exhibited moderate to strong correlation (Spearman ⍴ = 0.618–0.973) between tissue and EVs. Correlation in protein abundance was influenced by the extent of extra-hepatic expression of the target.

Conclusions
This study provides evidence that key proteins related to PK and PD profiles can be measured in liver-derived EVs and abundance of liver-enriched DMEs are robustly correlated between paired tissue and EVs. The robust detection of protein markers related to drug PD profile in MAFLD opens the possibility to track within-subject changes in MAFLD and lays the foundation for future development of a liver-derived EV liquid biopsy to assess markers of drug exposure and response in vivo.
Original languageEnglish
Pages (from-to)3146-3159
Number of pages14
JournalBritish Journal of Clinical Pharmacology
Volume90
Issue number12
Early online date30 Jul 2024
DOIs
Publication statusPublished - Dec 2024

Keywords

  • drug metabolism
  • extracellular vesicles
  • liver-derived EVs
  • Metabolic-associated fatty liver disease
  • proteomics
  • metabolic-associated fatty liver disease

Fingerprint

Dive into the research topics of 'Establishing the capacity to monitor proteins relevant to the study of drug exposure and response using liver-derived extracellular vesicles'. Together they form a unique fingerprint.

Cite this