Disposition and metabolism of [14C]PTZ601 in healthy volunteers

Abstract

1. Six healthy male subjects were given a single dose of 500 mg of [14C]PTZ601 (mean radioactivity 79.2 μCi) by intravenous (IV) infusion over 1 h, and observed for 5 days post-dose during which pharmacokinetic (PK) samples were collected. Plasma PTZ601 concentrations and metabolite identification were determined using LC-MS/MS; PK parameters were estimated by non-compartmental analysis. Excretion and mass balance were determined with liquid scintillation analysis and metabolites profiling was characterized by HPLC online radiochemical detection.2. The disposition of PTZ601 was best described by a fast absorption, followed by a biphasic elimination phase. Peak PTZ601 plasma concentrations were reached within 0.5–1 h. The mean elimination half-life was 1.6 h and clearance was 13 L/h.3. Recovery of the radioactivity dose was complete (mean 92%). The main route of excretion (parent and metabolites) was the renal route, as urine accounted for 69–77%, while feces only 13–22%, of the total radioactivity.4. The majority of the drug was excreted in urine as multiple open ring metabolites: M17.3 (oxidative ring-opened product) and M22.2 (di-cysteine conjugate of 17.3); unchanged PTZ601 in urine contributed to 15% of radioactivity. The major metabolites detected in plasma were M17.3, M12.8 (acetylated M17.3), M22.2, and M41.4 (methylated M17.3).5. PTZ601 was well tolerated.