50th Anniversary Celebration Collection Special Section on Drug Metabolism and Precision Medicine-Minireview Achieving a Deeper Understanding of Drug Metabolism and Responses Using Single-Cell Technologies

Recent advancements in single-cell technologies have enabled detec-tion of RNA, proteins, metabolites, and xenobiotics in individual cells, and the application of these technologies has the potential to transform pharmacological research. Single-cell data has already resulted in the development of human and model species cell atlases, identifying dif-ferent cell types within a tissue, further facilitating the characterization of tumor heterogeneity, and providing insight into treatment resistance. Research discussed in this review demonstrates that distinct cell popu-lations express drug metabolizing enzymes to different extents, indicat-ing there may be variability in drug metabolism not only between organs, but within tissue types. Additionally, we put forth the concept that single-cell analyses can be used to expose underlying variability in cellular response to drugs, providing a unique examination of drug effi-cacy, toxicity, and metabolism. We will outline several of these techni-ques: single-cell RNA-sequencing and mass cytometry to characterize and distinguish different cell types, single-cell proteomics to quantify drug metabolizing enzymes and characterize cellular responses to drug, capillary electrophoresis-ultrasensitive laser-induced fluores-cence detection and single-probe single-cell mass spectrometry for de-tection of drugs, and others. Emerging single-cell technologies such as these can comprehensively characterize heterogeneity in both cell -type-specific drug metabolism and response to treatment, enhancing progress toward personalized and precision medicine.SIGNIFICANCE STATEMENT Recent technological advances have enabled the analysis of gene expression and protein levels in single cells. These types of analy-ses are important to investigating mechanisms that cannot be elu-cidated on a bulk level, primarily due to the variability of cell populations within biological systems. Here, we summarize cell -type-specific drug metabolism and how pharmacologists can uti-lize single-cell approaches to obtain a comprehensive understand-ing of drug metabolism and cellular heterogeneity in response to drugs.