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Liquid Biopsy Enables Quantification of the Abundance and Interindividual Variability of Hepatic Enzymes and Transporters
Author(s) -
Achour Brahim,
AlMajdoub Zubida M.,
GrybosGajniak Agnieszka,
Lea Kristi,
Kilford Peter,
Zhang Mian,
Knight David,
Barber Jill,
Schageman Jeoffrey,
RostamiHodjegan Amin
Publication year - 2021
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.2102
Subject(s) - drug metabolism , liver biopsy , drug , dosing , biology , gene expression , in silico , genotyping , transporter , computational biology , medicine , pharmacology , biopsy , gene , genotype , pathology , genetics
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.