Metabolism and bioavailability aspects of natural products of plant origin using mass spectrometry-based and metabolomic approaches

Covering: 1982 to 2025The therapeutic value of natural products (NPs) is well established, as evidenced by their rich ethnopharmacological history and the significant proportion of marketed drugs derived from natural sources. Despite their notable advantages such as structural versatility and scaffold diversity, NPs have been increasingly sidelined by the pharmaceutical industry due to the labor-intensive nature of their isolation and structural elucidation as well as issues related to patenting, sustainable sourcing and preclinical evaluation. Moreover, current bioavailability research focuses predominantly on well-known medicinal and edible plants or specific compound classes, leaving many other promising candidates underexplored. The interplay between the gut microbiota and NPs, which is critical for pharmacokinetics and ADME (absorption, distribution, metabolism, and excretion), is also overlooked. Numerous <i>in vitro</i> and <i>in vivo</i> models have been developed to study the ADME properties of xenobiotics, while human clinical trials remain scarce in the field of NPs. Recent technological advancements, including innovations in mass spectrometry (MS), smart library screening, dereplication, molecular networking, and metabolomics, have significantly improved the NP research pipeline, offering faster and more accurate compound identification. High-resolution instruments like Orbitrap, QTOF, FT-ICR, and MRMS, alongside IMS and advanced data acquisition techniques (DDA and DIA), now offer deeper insights into complex mixtures. Despite MS being a cornerstone of pharmacokinetics-pharmacodynamics (PK/PD) studies, the integration of metabolomics and big data analytics remains underutilized, particularly in NP prioritization. This review aims to explore the evolution of MS in NP metabolism studies, from early investigations to current multidisciplinary approaches, proposing a critical reflection on the challenges in NP drug development.