Pharmacometabolomics uncovers key metabolic changes in the first-in-human study of β-lapachone derivative

• Published in: Metabolomics Vol. 21; no. 5; p. 122
• Main Authors: Jang, Yeonseo, Kang, Jihyun, Li, Yufei, Chae, Woori, Yang, Eunsol, Lee, SeungHwan, Cho, Joo-Youn
• Format: Journal Article
• Language: English
• Published: New York Springer US 19.08.2025; Springer Nature B.V
• Subjects: Adult; Biochemistry; Biomarkers - blood; Biomedical and Life Sciences; Biomedicine; Cell Biology; Chromatography; Correlation analysis; Developmental Biology; Enzymes; Female; Genotypes; Hepatitis; Humans; Inflammation; Lapachone; Life Sciences; Lipid metabolism; Male; Metabolic Networks and Pathways - drug effects; Metabolic pathways; Metabolism; Metabolites; Metabolome - drug effects; Metabolomics; Metabolomics - methods; Molecular Medicine; NAD(P)H Dehydrogenase (Quinone) - genetics; NAD(P)H Dehydrogenase (Quinone) - metabolism; NADPH dehydrogenase; Naphthoquinones - metabolism; Naphthoquinones - pharmacokinetics; Naphthoquinones - pharmacology; Original; Original Article; Pharmacodynamics; Plasma; Side effects; Statistical analysis; Therapeutic targets; Toxicity; Variance analysis; Young Adult; United States > US; Austria; NQO1; Metabolites; WK0202; Nrf2; Arginine biosynthesis
• ISSN: 1573-3890; 1573-3882; 1573-3890
• DOI: 10.1007/s11306-025-02332-1

Introduction WK0202, a β-lapachone derivative under clinical development, activates NAD(P)H quinone dehydrogenase 1 (NQO1), acting as a detoxifying and antioxidant agent. In this study, a metabolomics investigation of β-lapachone derivatives in humans is performed to characterize drug-induced alterations in endogenous metabolic pathways. Objectives This study investigated metabolic alterations induced by WK0202 administration and their potential association with its therapeutic mechanism and efficacy. Using targeted and untargeted metabolomics approaches, we identified potential pharmacodynamic biomarker candidates that may reflect the drug’s activity and metabolic effects. Methods Plasma samples from healthy subjects who received multiple doses of WK0202 were compared with a placebo control group. The metabolomic profiles were compared pre- and post-dose to identify significant metabolic changes. Significant metabolites were identified using statistical analyses, focusing on key metabolic pathways. To further investigate NQO1 genotype effects, Spearman correlation analysis was performed between post/pre-dose concentration ratios and genotypes. Results Following WK0202 administration, significant changes were observed in the alanine, aspartate and glutamate metabolism, arginine biosynthesis, and lipid metabolism. Although most metabolites were not strongly dependent on NQO1 genotype or dose group, they exhibited an overall consistent trend. These alterations were indicative of Nrf2 pathway activation, possibly by NQO1-mediated drug activity. Conclusion These metabolic alterations highlight the potential of endogenous metabolites as surrogate markers for identifying novel therapeutic targets and assessing the efficacy of WK0202 in future clinical studies.