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

Abstract

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 (t1/2) at 17.03 hour, the area under curve value (AUC) of 1451.82 ng/ml*h, and the maximum plasma concentration (Cmax) 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.

Inhibition of Histone Demethylases LSD1 and UTX Regulates ERα Signaling in Breast Cancer

“…Interestingly, many patients who relapse on tamoxifen therapy will respond to different ERα downregulators (e.g., fulvestrant), acting as selective endocrine receptor disruptor (SERD) [7]. The majority of tamoxifen-resistant ERα-positive BC is still sensitive to fulvestrant, although it requires intramuscular injection, and a complex dosing schedule, limiting its application in a neoadjuvant setting [8][9][10]. Current research for SERD molecules in BC seems more promising, due to their intrinsic property of inducing only limited phenomena of resistance.…”

Metabolism and Pharmacokinetic Study of the Boron-Containing Prodrug of Belinostat (ZL277), a Pan HDAC Inhibitor with Enhanced Bioavailability

“…The incubation of ZL277 with liver S9 fractions followed the procedures of incubation with liver microsomes, as described previously [23]. The pre-incubation solution consisted of 30 µL of potassium phosphate buffer (pH 7.4; 10X), 241.5 µL water, 15 µL of NADPH solution A, 3 µL of NADPH solution B, 7.5 µL rat liver S9 fractions.…”

“…The incubation of ZL277 with microsomes followed the similar procedures for studying glucuronidation of ZB716 [23]. The mixture of 205.5 µL water, 24 µL of UGT Reaction Mix solution A, 60 µL of UGT Reaction Mix solution B, and 7.5 µL rat liver microsomes was incubated at 37 • C for 5 min.…”

“…The incubation of ZL277 with liver cytosols followed a similar procedure to the study of sulfation of ZB716 [23]. After termination of incubation with 300 µL MeOH, the final mixture was centrifuged.…”

“…Plasma, urine, or feces samples were processed following protocols published previously [23]. These samples were injected on the Hypersil GOLD C18 column (1.8 µm, 2.1 × 50 mm) with UHPLC ultimate 3000 from Dionex, coupled with a TSQ Voltage mass spectrometer, to quantitate the concentration of the main metabolites of ZL277.…”