Dataset Information

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

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.

SUBMITTER: Achour B

PROVIDER: S-EPMC7839483 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Achour Brahim B Al-Majdoub Zubida M ZM Grybos-Gajniak Agnieszka A Lea Kristi K Kilford Peter P Zhang Mian M Knight David D Barber Jill J Schageman Jeoffrey J Rostami-Hodjegan Amin A

Clinical pharmacology and therapeutics 20201125 1

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 bio ...[more]

PMID: 33141922

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Project description:The microbiome and pregnancy are known to alter drug disposition, yet the interplay of the two physiologic factors on the expression and/or activity of drug metabolizing enzymes and transporters (DMETs) is unknown. This study investigated the effects of microbiome on host hepatic DMETs in mice during pregnancy by comparing four groups of conventional (CV) and germ-free (GF) female mice and pregnancy status, namely, CV nonpregnant, GF non-pregnant, CV pregnant, and GF pregnant mice. Transcriptomic and targeted proteomics of hepatic DMETs were profiled by using multiomics. Plasma bile acid and steroid hormone levels were quantified by liquid chromatography tandem mass spectrometry. CYP3A activities were measured by mouse liver microsome incubations. The trend of pregnancy-induced changes in the expression or activity of hepatic DMETs in CV and GF mice was similar; however, the magnitude of change was noticeably different. For certain DMETs, pregnancy status had paradoxical effects on mRNA and protein expression in both CV and GF mice. For instance, the mRNA levels of Cyp3a11, the murine homolog of human CYP3A4, were decreased by 1.7-fold and 3.3-fold by pregnancy in CV and GF mice, respectively; however, the protein levels of CYP3A11 were increased similarly ∼twofold by pregnancy in both CV and GF mice. Microsome incubations revealed a marked induction of CYP3A activity by pregnancy that was 10-fold greater in CV mice than that in GF mice. This is the first study to show that the microbiome can alter the expression and/or activity of hepatic DMETs in pregnancy. SIGNIFICANCE STATEMENT: We demonstrated for the first time that microbiome and pregnancy can interplay to alter the expression and/or activity of hepatic drug metabolizing enzymes and transporters. Though the trend of pregnancy-induced changes in the expression or activity of hepatic drug metabolizing enzymes and transporters in conventional and germ-free mice was similar, the magnitude of change was noticeably different.

Dataset Information

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

Publications

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

Similar Datasets

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