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

Autor: Jill Barber, Peter Kilford, Amin Rostami-Hodjegan, Mian Zhang, Brahim Achour, Agnieszka Grybos‐Gajniak, David Knight, Kristi Lea, Jeoffrey Schageman, Zubida M. Al-Majdoub
Rok vydání: 2020
Předmět:
Adult
Liver/metabolism
Male
Drug
Cytochrome P-450 Enzyme System/metabolism
Metabolic Clearance Rate
media_common.quotation_subject
In silico
Exosomes
Bioinformatics
030226 pharmacology & pharmacy
Article
Metabolic Clearance Rate/physiology
Variable Expression
Young Adult
03 medical and health sciences
0302 clinical medicine
Cytochrome P-450 Enzyme System
Inactivation
Metabolic/physiology
Membrane Transport Proteins/metabolism
Humans
Medicine
Pharmacology (medical)
Liquid biopsy
Gene
Genotyping
Biological Transport/physiology
Aged
media_common
Aged
80 and over
Pharmacology
business.industry
Research
Liquid Biopsy
Membrane Transport Proteins
Biological Transport
Articles
Liquid Biopsy/methods
Middle Aged
Exosomes/metabolism
Liver
Drug development
030220 oncology & carcinogenesis
Inactivation
Metabolic
Female
business
Drug metabolism
Zdroj: Achour, B, Al-Majdoub, Z, Grybos-Gajniak, A, Lea, K, Kilford, P, Zhang, M, Knight, D, Barber, J, Schageman, J & Rostami-Hodjegan, A 2021, ' Liquid Biopsy Enables Quantification of the Abundance and Interindividual Variability of Hepatic Enzymes and Transporters ', Clinical Pharmacology & Therapeutics, vol. 109, no. 1, pp. 222-232 . https://doi.org/10.1002/cpt.2102
Clinical Pharmacology and Therapeutics
ISSN: 1532-6535
0009-9236
DOI: 10.1002/cpt.2102
Popis: 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. Whilst 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 employed 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 (SF) 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 enrolment in clinical trials and for patient stratification in clinical practice to achieve more precise individual dosing.
Databáze: OpenAIRE
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