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Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro

Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro

Published on: January 31, 2022

A hydrophilic interaction UPLC-MS/MS quantitative method for the quantification of saracatinib in the human liver

Mohamed W Attwa¹, Adnan A Kadi¹

¹Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. mzeidan@ksu.edu.sa.

Analytical Methods : Advancing Methods and Applications

|February 11, 2026

Abstract:

Saracatinib (AZD-0530; SRB) is a pharmaceutical agent produced by AstraZeneca and is currently undergoing clinical studies. It is classified as a dual-kinase inhibitor, exhibiting selective activity both as an Src inhibitor and a Bcr-Abl tyrosine kinase inhibitor. No metabolic stability study for SRB has been reported; hence, so the goal of the present study was to establish an ultra-fast, green, sensitive, and validated UPLC-MS/MS method for the quantification of SRB levels in human liver microsomes (HLMs) using different in silico software to support the practical outcomes. The validated approach was used to estimate the SRB metabolic stability in HLMs. In silico software tools were employed to predict the potential sites of metabolic lability and toxicity within the SRB structure. SRB and baricitinib, used as an internal standard (IS), were isolated from HLMs using protein precipitation with acetonitrile (ACN) as the extracting agent. Chromatographic separation was conducted utilizing a Luna 3 µm HILIC column (200 Å: 50 × 2 mm, Ea), with the mobile phase comprising 0.1% formic acid in ACN (85%) and 10 mM ammonium formate in water (15% at pH 3.2), and the total run time was 1.0 min. SRB and IS were analyzed utilizing the MRM mass analyzer mode. The approach was validated according to the latest FDA guidelines for bioanalytical method validation. The SRB calibration curve demonstrated significant sensitivity, with a range of statistical linearity from 1 to 4000 ng mL^-1. The intraday and interday accuracies of the four quality controls varied from -4.17% to 12.25% and -3.92% to 13.50%, respectively. The metabolic stability parameters, including the in vitro half-life (t_1/2) and intrinsic clearance (Cl_int) of SRB, were assessed at 17.24 min and 47.02 mL min^-1 kg^-1, respectively. In silico research indicated that slight structural modifications to the N-methyl piperazine ring in the drug design may enhance metabolic stability and safety compared with those of SRB.

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