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Epristeride, a novel noncompetitive inhibitor of Type II 5α-reductase, has emerged as a potential therapeutic alternative for benign prostatic hyperplasia (BPH). Given that other 5α-reductase inhibitors, such as finasteride and dutasteride, are already monitored for their potential impact on doping control, comprehensive metabolic studies of epristeride are crucial for antidoping. This study investigates the metabolic pathways and metabolites of epristeride using in vitro microsome models, offering preliminary insights into the pharmacokinetics of this drug. Metabolite profiling was performed using liquid chromatography-high resolution mass spectrometry (LC-HRMS), with data acquisition facilitated by Xcalibur 4.2 software and metabolite identification facilitated by Compound Discoverer 3.3. By employing network pharmacology, the potential targets of epristeride are predicted. The binding energy is calculated using AutoDock Vina software to predict its impact on steroid metabolism. The study proposed three primary metabolites of epristeride: two Phase I oxidation products (M1 and M2) and one Phase II glucuronidation product (M3). Pathway analysis revealed that among the five CYP450 isoforms examined, CYP3A4 played a dominant role. The docking results tentatively elucidated five key target proteins (ESR1, CYP19A1, STAT3, AKR1C3, and CYP17A1) with low binding energies, indicating stable interactions. Notably, Phase I metabolites (M1 and M2) showed significant binding potential with these targets, whereas the Phase II metabolite (M3) exhibited lower binding stability. These findings provide a detailed understanding of epristeride's metabolic pathways and its potential biological impacts, offering valuable insights for monitoring its presence as a confounding factor in doping control.
Li et al. (Sun,) studied this question.