Pharmacokinetics, mass balance, and metabolism of [14C]SPH3127 (sitokiren), a novel direct renin inhibitor in humans.

INTRODUCTION: SPH3127 (Sitokiren), a novel direct renin inhibitor used to treat hypertension, is currently approved for marketing in China. The primary objective of this study was to determine the pharmacokinetics, mass balance, and biotransformation of [14C]SPH3127 in humans after the drug was administered to healthy Chinese male subjects. METHODS: The absorption, metabolism, and excretion of SPH3127 were characterised via isotope labeling technology in six healthy Chinese male subjects after receiving a single 100 mg oral dose of [14C]SPH3127 (100 μCi). RESULTS: SPH3127 was rapidly absorbed, with median Tmax values of 0.417 and 0.75 h observed for the parent drug and total radioactivity in human plasma. The arithmetic mean plasma half-life (t1/2) was approximately 4.83 h for SPH3127-related material. After 192 h of dosing, the mean cumulative excreted radioactivity was 101.66% of the dose, with 44.35% in urine and 57.31% in feces, indicating that urinary and fecal excretions were comparable and served as the primary elimination routes. Metabolite profiling revealed that the parent drug was detected in plasma, as well as in feces and urine. Twelve major metabolites in plasma, urine, and feces were analysed and identified. The principal metabolic pathways involved oxidation, dehydrogenation, hydrolysis, glucuronidation, and sulfation. SPH3127 was found to be safe, with no serious adverse events reported. CONCLUSION: SPH3127 showed favourable pharmacokinetic characteristics and safety profiles in this study. SPH3127 was rapidly absorbed and extensively metabolized in humans. The main excretion route of SPH3127 and its metabolites was through urine and feces. CLINICAL TRIAL REGISTRATION: http://www.chinadrugtrials.org.cn/, identifier CTR20222187.