TY - JOUR T1 - Profiling of Drug-Metabolizing Enzymes and Transporters in Human Tissue Biopsy Samples; A Review of the Literature JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.262972 SP - jpet.119.262972 AU - A. David Rodrigues AU - Andrew Rowland Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/12/26/jpet.119.262972.abstract N2 - Within the drug pharmacokinetics-absorption, distribution, metabolism and excretion (PK-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 pharmacokinetics (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, while 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 multi-organ axes (e.g., microbiome-gut-liver-kidney) and interest in remote sensing (inter-organ communication), it is envisioned that there will be increased demand for single and multi-organ tissue biopsy data to support hypothesis testing and PK-ADME model building.SIGNIFICANCE STATEMENT With the advent of physiologically-based PK (PBPK) modeling, researchers now have a greater appreciation for the various ADME-related processes, involving multiple organs, and their net impact on a drug’s PK profile. Therefore, it is not surprising that such modeling has galvanized the development of companion tools like extensively humanized rodents and multi-organ microphysiological systems. With the reported utility of conventional tissue biopsy as precedent, it is envisioned that attention will also turn to less invasive “liquid biopsy” methods in support of ADME-related studies (e.g., the profiling of immunocaptured cargo-laden tissue-specific nanovesicles present in human blood). Generation of such multi-organ liquid biopsy data, in larger numbers of subjects and at multiple study time points, will provide a rich dataset for modeling purposes. ER -