Liquid Biopsy Enables Quantification of the Abundance and Interindividual Variability of Hepatic Enzymes and Transporters

Brahim Achour, Zubida Al-Majdoub, Agnieszka Grybos‐Gajniak, Kristi Lea, Peter Kilford, Mian Zhang, David Knight, Jill Barber, Jeoffrey Schageman, Amin Rostami-Hodjegan

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Abstract

Variability in individual capacity for hepatic elimination of therapeutic drugs is well recognized and is associated with variable expression and activity of liver enzymes and transporters. Although genotyping offers some degree of stratification, there is often large variability within the same genotype. Direct measurement of protein expression is impractical due to limited access to tissue biopsies. Hence, determination of variability in hepatic drug metabolism and disposition using liquid biopsy (blood samples) is an attractive proposition during drug development and in clinical practice. This study used a multi-“omic” strategy to establish a liquid biopsy technology intended to assess hepatic capacity for metabolism and disposition in individual patients. Plasma exosomal analysis (n = 29) revealed expression of 533 pharmacologically relevant genes at the RNA level, with 147 genes showing evidence of expression at the protein level in matching liver tissue. Correction of exosomal RNA expression using a novel shedding factor improved correlation against liver protein expression for 97 liver-enriched genes. Strong correlation was demonstrated for 12 key drug-metabolizing enzymes and 4 drug transporters. The developed test allowed reliable patient stratification, and in silico trials demonstrated utility in adjusting drug dose to achieve similar drug exposure between patients with variable hepatic elimination. Accordingly, this approach can be applied in characterization of volunteers prior to enrollment in clinical trials and for patient stratification in clinical practice to achieve more precise individual dosing.
Original languageEnglish
Pages (from-to)222-232
Number of pages11
JournalClinical Pharmacology & Therapeutics
Volume109
Issue number1
Early online date3 Nov 2020
DOIs
Publication statusPublished - 1 Jan 2021

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Biological Transport/physiology
  • Cytochrome P-450 Enzyme System/metabolism
  • Exosomes/metabolism
  • Female
  • Humans
  • Inactivation, Metabolic/physiology
  • Liquid Biopsy/methods
  • Liver/metabolism
  • Male
  • Membrane Transport Proteins/metabolism
  • Metabolic Clearance Rate/physiology
  • Middle Aged
  • Young Adult

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