Evaluation of Niraparib Metabolic Stability in Human Liver Microsomes Using Ultrafast UPLC‐MS/MS Technique: In Silico Screening for Structural Alerts Related to the Metabolic Lability and In Silico DEREK Toxicity

Niraparib (Zejula; NRP) is a potent, orally bioavailable poly (ADP-ribose) polymerase inhibitor that has been approved by the US FDA. The aim of this study was to establish a specific, fast, sustainable, and dependable UPLC-MS/MS procedure for measuring NRP in HLMs matrix, used to compute the metabolic stability of NRP. The established approach was validated using human liver microsomes (HLMs) matrix across a level range of 1-3000 ng/mL. The intraday and interday precision and accuracy rates ranged between -3.95% and 7.58%, and -2.00% and 8.79%, respectively. The MS/MS analysis was performed in a positive ESI ionization mode, whereas chromatography employed an SB-C18 column with 1-min run time. The StarDrop software involved P450 and DEREK modules that were employed for the evaluation of metabolic lability and NRP structural alarms, respectively. The in vitro half-life was determined to be 33.81 min, and the intrinsic clearance of NRP was measured at 23.98 mL/min/kg. In silico assessment indicates that small structural modifications to the piperidine ring (96%) and the indazole moiety (3%) in drug design could increase the NRP metabolic stability. The assessment of in silico ADME and metabolic stability properties is necessary for progressing novel drug studies aimed at improving metabolic stability.