Drug Design, Development and Therapy (Oct 2020)
LC-MS/MS Estimation of the Anti-Cancer Agent Tandutinib Levels in Human Liver Microsomes: Metabolic Stability Evaluation Assay
Abstract
Mohamed W Attwa, Ali S Abdelhameed, Nasser S Al-Shakliah, Adnan A Kadi 1 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaCorrespondence: Ali S AbdelhameedDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi ArabiaTel +966 1146 70237Fax +966 1146 76220Email [email protected]: Tandutinib (MLN518 or CT 53518) (TND) is a novel, oral, small-molecule inhibitor of type III receptor tyrosine kinases utilized for the treatment of acute myeloid leukemia (AML).Materials and Methods: In silico prediction of hepatic drug metabolism for TND was determined using the StarDrop® WhichP450™ module to confirm its metabolic liability. Second, an efficient and accurate LC-MS/MS method was established for TND quantification to evaluate metabolic stability. TND and entrectinib (ENC) (internal standard; IS) were resolved using an isocratic elution system with a reversed stationary phase (C8 column).Results: The established LC-MS/MS method exhibited linearity (5– 500 ng/mL) with r2 ≥ 0.9999 in the human liver microsomes matrix. The method sensitivity was indicated by the limit of quantification (3.8 ng/mL), and reproducibility was revealed by inter- and intraday precision and accuracy (below 10.5%). TND metabolic stability estimation was calculated using intrinsic clearance (22.03 μL/min/mg) and in vitro half-life (29.0 min) values.Conclusion: TND exhibited a moderate extraction ratio indicative of good bioavailability. According to the literature, the approach developed in the present study is the first established LC-MS/MS method for assessing TND metabolic stability.Keywords: tandutinib, metabolic stability assessment, in vitro half-life, validated LC-MS/MS methodology
