Development and validation of LC-MS/MS method for quantification of novel PP2A – β-catenin signalling inhibitor, S011-2111 in mice plasma: Application to its preclinical pharmacokinetic studies

Abstract

S011-2111 is a semicarbazone and chalcone hybrid demonstrating antiproliferative tumor cell-selective effects along with unique antimetastatic potential by mitigating PP2A-β-catenin signalling pathway. The present study envisaged to explore the in vitro and in vivo pharmacokinetics of S011-2111. A sensitive and selective liquid chromatography-tandem mass spectrometry bioanalytical method was developed and validated to determine S011-2111. It has high permeability across intestinal membrane as observed in in situ single-pass intestinal perfusion study. It has high plasma protein binding and poor aqueous solubility. It was rapidly partitioning into plasma of blood, where it was moderately stable. In mice liver microsomal stability study, S011-2111 was stable against cytochrome P450 enzymes but undergoes rapid glucuronidation with intrinsic clearance of 148.6 ± 48.3 µL/min/mg. Following 100 mg/kg oral dosing of S011-2111, the compound was detectable in the plasma samples up to 24 h with a maximum plasma concentration of 45 ± 16.5 ng/mL at 2.4 ± 0.1 h and absolute bioavailability of 1.68%. Knowledge from this research will assist in further development of S011-2111 as an anti-cancer agent.