Innovations, Opportunities, and Challenges for Predicting Alteration in Drug-Metabolizing Enzyme and Transporter Activity in Specific Populations

Received September 7, 2023; accepted September 28, 2023 ABSTRACT Drug-metabolizing enzymes and transporters (DMETs) are key reg-ulators of the pharmacokinetics, efficacy, and toxicity of therapeu-tics. Over the past two decades, significant advancements in in vitro methodologies, targeted proteomics, in vitro to in vivo ex-trapolation methods, and integrated computational approaches such as physiologically based pharmacokinetic modeling have un-equivocally contributed to improving our ability to quantitatively predict the role of DMETs in absorption, distribution, metabolism, and excretion and drug-drug interactions. However, the paucity of data regarding alterations in DMET activity in specific populations such as pregnant individuals, lactation, pediatrics, geriatrics, or-gan impairment, and disease states such as, cancer, kidney, and liver diseases and inflammation has restricted our ability to realize the full potential of these recent advancements. We envision that a series of carefully curated articles in a special supplementary issue of Drug Metabolism and Disposition will summarize the latest pro-gress in in silico, in vitro, and in vivo approaches to characterize alteration in DMET activity and quantitatively predict drug disposi-tion in specific populations. In addition, the supplementary issue will underscore the current scientific knowledge gaps that present formidable barriers to fully understand the clinical implications of altered DMET activity in specific populations and highlight oppor-tunities for multistakeholder collaboration to advance our collec-tive understanding of this rapidly emerging area. SIGNIFICANCE STATEMENT This commentary highlights current knowledge and identifies gaps and key challenges in understanding the role of drug-metabolizing enzymes and transporters (DMETs) in drug disposition in specific populations. With this commentary for the special issue in Drug Metabolism and Disposition, the authors intend to increase interest and invite potential contributors whose research is focused or has aided in expanding the understanding around the role and impact of DMETs in drug disposition in specific populations.