Profiling of Drug-Metabolizing Enzymes and Transporters in Human Tissue Biopsy Samples: A Review of the Literature

Abstract

Within the drug pharmacokinetics (PK)-absorption, distribution, metabolism, and excretion (ADME) research community, investigators regularly generate in vitro data sets using appropriately vendor-sourced and processed human tissue. Such data enable drug screening, the generation of kinetic parameters, extrapolation of in vitro to in vivo, as well as the modeling and simulation of drug PK. Although there are large numbers of manuscripts describing studies with deceased organ donor tissue, relatively few investigators have published studies utilizing living donor tissue biopsy samples. After a review of the available literature, it was possible to find publications describing the use of tissue biopsy samples to determine enzyme inhibition ex vivo, the study of genotype-phenotype associations, the evaluation of tissue expression profiling following an inducer, and assessment of correlations between tissue expression profiles and in vivo-derived trait measures (e.g., biomarker plasma levels and probe drug PK). Some reports described multiple single-tissue biopsies, whereas others described single multiple-organ biopsies. It is concluded that biopsy-derived data can support modeling exercises (as input data and when validating models) and enable the assessment of organ-specific changes in enzyme and transporter profiles resulting from drug interactions, disease (e.g., metabolic disease, fibrosis, inflammation, cancer, infection), age, pregnancy, organ impairment, and genotype. With the emergence of multiorgan axes (e.g., microbiome-gut-liverkidney) and interest in remote sensing (interorgan communication), it is envisioned that there will be increased demand for single-and multiorgan tissue biopsy data to support hypothesis testing and PK-ADME model building. SIGNIFICANCE STATEMENTBased on a review of the literature, it is apparent that profiling of human tissue biopsy samples is useful in support of pharmacokinetics (PK)-absorption, distribution, metabolism, and excretion (ADME)-related studies. With conventional tissue biopsy as precedent, it is envisioned that researchers will turn to less invasive "liquid biopsy" methods in support of ADME-related studies (e.g., profiling of plasma-derived tissue-specific nanovesicles). Generation of such multiorgan liquid biopsy data in larger numbers of subjects and at multiple study time points will provide a rich data set for modeling purposes.

Exploring the Use of Serum‐Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Hepatic Cytochromes P450 and Organic Anion Transporting Polypeptides

“…Most recently, attention has turned to plasma and serum‐derived extracellular vesicles (EVs) as liquid biopsy ( Figure ). This is because various EVs are shed into the blood and contain cargo that is representative of their tissue of origin 3,5,7,20 . Therefore, the aim of the present study was to build upon earlier efforts 5 and prepare liver‐derived EVs from the serum samples of two small ( N = 5 subjects) RIF studies, and retrospectively subject them to proteomic analysis to investigate the induction of P450s and OATPs.…”

Leveraging Human Plasma‐Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Cytochrome P450 3A4 by Modafinil

“…Additionally, rifampicin is known to induce gut P-glycoprotein, which was not considered in any of the modeling exercises. 51,52 Two of the five modeled victim drugs (17α-ethinylestradiol and abemaciclib) have been described as Pglycoprotein substrates (Supplemental Methods).…”

Gene Expression and Protein Abundance of Nuclear Receptors in Human Intestine and Liver: A New Application for Mass Spectrometry-Based Targeted Proteomics

“…In addition, several clinical DDI studies indicate that the extent of interaction, i.e., reduction of systemic drug exposure of victim drugs, is markedly affected by the route of administration of the perpetrator drug (e.g., rifampicin). In this regard, the oral administration of nuclear receptor ligands and the victim drug (substrates of CYP3A4 and/or P-gp) caused strikingly lower plasma levels (i.e., higher degree of interaction) compared to the intravenous administration of the victim drug [ 18 , 24 , 25 , 26 , 27 , 28 ]. Finally, some nuclear receptor ligands such as efavirenz were shown to induce only hepatic, but not intestinal, DMEs and drug transporters [ 29 , 30 ].…”

“…A few studies demonstrating direct in vivo evidence for the regulation of human DMEs and drug transporters have been conducted in human intestinal tissue after oral administration of PXR ligands [ 17 , 18 ]. In these studies, nuclear receptor-mediated upregulation of intestinal drug transporters (e.g., P-gp, MRP2) or DMEs (e.g., CYP3A4, UGT1A1) resulted in markedly diminished plasma exposure of co-administered victim drugs.…”

“…The same is true for the distinct tissue concentrations of ligands required for a pronounced activation of the nuclear receptors. The available expression data indicate substantial expression differences between tissues, which may translate to differences in induction potential of prototypical inducers in different organs, related to their binding affinity to different nuclear receptors and the respective expression profile of nuclear receptors [ 18 , 22 ]. However, available expression data are exclusively based on mRNA data, which may not necessarily correlate to the encoded proteins, i.e., the nuclear receptors [ 21 ].…”