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?

It is now established that a drug's pharmacokinetics (PK) absorption, distribution, metabolism, excretion (ADME) and drug-drug interaction (DDI) profile can be modulated by age, disease, and genotype. In order to facilitate subject phenotyping and clinical DDI assessment, therefore, various endogenous compounds (in plasma and urine) have been pursued as drug-metabolizing enzyme and transporter biomarkers. Compared with biomarkers, however, the topic of circulating extracellular vesicles as "liquid biopsy" has received little attention within the ADME community; most organs secrete nanovesicles (e.g., exosomes) into the blood that contain luminal "cargo" derived from the originating organ (proteins, messenger RNA, and microRNA). As such, ADME profiling of plasma exosomes could be leveraged to better define genotype-phenotype relationships and the study of ontogeny, disease, and complex DDIs. If methods to support the isolation of tissue-derived plasma exosomes are successfully developed and validated, it is envisioned that they will be used jointly with genotyping, biomarkers, and modeling tools to greatly progress translational PK-ADME-DDI science.