ArticleClinical pharmacology and therapeutics2025
From Discovery to Translation: Endogenous Substrates of OAT1 and OAT3 as Clinical Biomarkers for Renal Secretory Function.
Article in Clinical pharmacology and therapeutics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Pediatric Developmental Safety Assessment and New Approach Methodologies: US FDA/Triangle CERSI Workshop Report.Clinical pharmacology and therapeutics · 2026Review
- Untargeted Metabolomics Reveal New Endogenous Plasma Biomarkers Associated with CYP3A Inhibition in Humans.Clinical pharmacology and therapeutics · 2026Article
- Effect of Late Second to Early Third Trimester of Pregnancy on the Activity of Renal Organic Anion Transporters (OAT1 and OAT3): A Biomarker Study.Clinical pharmacology and therapeutics · 2026Article
- Predicting Pharmacokinetic Variability and Drug Interaction Risk Using Omics-Based Biomarkers.Clinical and translational science · 2026Review
- Population Physiologically-Based Pharmacokinetic Modeling to Determine Ontogeny: A Quantitative Clinical Pharmacology Example in Pediatric Rare Disease.CPT: pharmacometrics & systems pharmacology · 2026Review
- Ginger and Its Purified Major Components Inhibit Clinically Relevant Uptake and Efflux Transporters In Vitro.Pharmaceutics · 2026Article
- Tubular secretion in chronic kidney disease: from established physiology to clinical utility.Frontiers in cell and developmental biology · 2026Review
- Drug-drug interactions in targeted cancer therapies: a focus on tyrosine kinase inhibitors.Expert review of clinical pharmacology · 2025Review
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
The recent ICH M12 guidance on Drug Interaction Studies encourages the use of alternate approaches for predicting drug-drug interaction (DDI) potential of new chemical entities. One approach involves the use of endogenous substrates of drug metabolizing enzymes and transporters (DMET) as biomarkers, which can assess the inhibitory potential of new chemical entities towards DMET during Phase 1 clinical studies. Thus, biomarkers could potentially eliminate the need for dedicated DDI studies with exogenous probe substrates. Metabolomics, in conjunction with in vitro and/or in vivo preclinical models or clinical studies, can be used for biomarker discovery. We developed and applied a novel metabolomics-based DMET biomarker discovery (MDBD) approach to identify and qualify biomarkers of renal organic anion transporter 1 (OAT1) and OAT3. Untargeted metabolomics of pooled plasma and urine samples (n = 16) from a pharmacokinetic DDI study using the OAT1/3 inhibitor, probenecid, yielded 153 features identified as putative OAT1/3 biomarkers. Subsequently, in vitro transporter uptake assays using processed urine samples confirmed 57 of these features as OAT1 and/or OAT3 substrates. Finally, 23 features were clinically validated as OAT1/3 biomarkers through a detailed pharmacokinetic analysis (0-24 h) of plasma and urine samples (n = 4). These biomarkers, either alone or as part of a panel, can predict OAT1/3-mediated DDIs and interindividual variability in the renal secretory clearance of organic anions across different populations, thereby enabling translational utility in clinical settings. The novel MDBD approach can be extended to discover biomarkers of enzymes and other transporters.
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