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ZB716 is a selective estrogen receptor downregulator (SERD) with excellent oral bioavailability and superior efficacy. In this study, we investigate the in vitro and in vivo metabolism and the pharmacokinetics of ZB716 by incubation with liver microsomes, liver cytosol, and by orally dosing rodents. Metabolic products were identified and quantified by a combination of liquid chromatography and tandem +mass spectrometry. The metabolic profile of ZB716 showed fulvestrant and ZB716-sulfone as the two major oxidative metabolites. ZB716 also underwent some degree of sulfation and glucuronidation in vitro . The major oxidative metabolites of ZB716 were found in rat plasma, feces, and urine samples. No sulfation and glucuronidation metabolites from ZB716 were found in plasma. Limited amounts of sulfate conjugates and glucuronides of ZB716 were detected in feces. The glucuronidation on 3-OH position of fulvestrant was the main metabolite found in urine, suggesting that this specific site of phase 2 metabolism is blocked in ZB716 and formation of glucuronide 3-fulvestrant must be preceded by metabolic transformation of ZB716 to fulvestrant. The pharmacokinetic study of ZB716 showed a half-life (t 1/2 ) at 17.03 hour, the area under curve value (AUC) of 1451.82 ng/ml*h, and the maximum plasma concentration (C max ) at 158.12 ng/mL reached at 2 h after a single dose of 10 mg/kg by oral gavage. Overall this study elucidated important metabolic characteristics of ZB716, an oral SERD that has demonstrated superior bioavailability and efficacy in preclinical studies conducted so far.

Metabolism, pharmacokinetics, and bioavailability of ZB716, a Steroidal Selective Estrogen Receptor Downregulator (SERD)