Various clinical tools have been developed to support the study of genotype-phenotype associations and drug-drug interactions (DDI) involving drug-metabolizing enzymes (e.g., cytochromes P450, CYP) and drug transporters. These have included probe drugs, probe drug cocktails, micro-dosing, tissue imaging reagents, and endogenous compounds in plasma and urine that present as biomarkers. More recently, attention has turned to “liquid biopsy” methods, which involve the profiling (proteomics and CYP activity) of immunocaptured cargo-laden and tissue-specific extracellular vesicles (EV) present in human blood. The presentation will describe the isolation, characterization, and profiling of serum EV (mixtures of exosomes and small microvesicles) in support of CYP and organic anion transporting polypeptide (OATP) profiling. Examples include CYP2D6 genotype-phenotype associations, CYP3A5 genotype-liver protein expression profiling, differentiation of gut CYP1A2 versus CYP3A4 activity, induction profiling (liver CYP3A4, CYP2D6, OATP1B1, and OATP1B3) following an inducer (rifampicin), and expression profiling of serum-derived liver EV from pregnant versus non-pregnant females. With further validation and wider use, it is envisioned that the EV-based liquid biopsy approach will be deployed alongside established drug probe-based methods and emergent drug transporter biomarkers. Such advancements are warranted because of the absence of CYP biomarkers (beyond CYP3A4/5), increasingly complex DDI involving gut and/or liver CYP3A4/5, and questions regarding transporter induction.
Plasma extracellular nanovesicle (exosome)-derived biomarkers for drug metabolism pathways: a novel approach to characterize variability in drug exposure. Rowland A, Ruanglertboon W, van Dyk M, Wijayakumara D, Wood LS, Meech R, Mackenzie PI, Rodrigues AD, Marshall JC, Sorich MJ. Br J Clin Pharmacol. 2019 Jan;85(1):216-226.
Profiling of Drug-Metabolizing Enzymes and Transporters in Human Tissue Biopsy Samples: A Review of the Literature. Rodrigues AD, Rowland A. J Pharmacol Exp Ther. 2020 Mar;372(3):308-319.
Induction of Human Intestinal and Hepatic Organic Anion Transporting Polypeptides: Where Is the Evidence for Its Relevance in Drug-Drug Interactions? Rodrigues AD, Lai Y, Shen H, Varma MVS, Rowland A, Oswald S. Drug Metab Dispos. 2020 Mar;48(3):205-216.
From Endogenous Compounds as Biomarkers to Plasma-Derived Nanovesicles as Liquid Biopsy; Has the Golden Age of Translational Pharmacokinetics-Absorption, Distribution, Metabolism, Excretion-Drug-Drug Interaction Science Finally Arrived? Rodrigues D, Rowland A. Clin Pharmacol Ther. 2019 Jun;105(6):1407-1420.
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. Rodrigues AD, van Dyk M, Sorich MJ, Fahmy A, Useckaite Z, Newman LA, Kapetas AJ, Mounzer R, Wood LS, Johnson JG, Rowland A. Clin Pharmacol Ther. 2021 Apr 1. doi: 10.1002/cpt.2244. Online ahead of print