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.