Year: 2025
Type: article
Abstract: In the context of cancer treatment, the employment of multiple drug therapies frequently results in a high prevalence of drug-drug interaction (DDI) in clinical practice. Crizotinib is a tyrosine kinase inhibitor (TKI) used to treat non-small cell lung cancer (NSCLC). Tropifexor is a Farnesoid X Receptor (FXR) agonist used to treat non-alcoholic steatohepatitis (NASH) and other metabolic disorders. This study developed an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the quantitative determination of crizotinib and 2-Keto crizotinib concentrations and investigated the effect of tropifexor on crizotinib metabolism. Results showed good linearity for crizotinib and 2-Keto crizotinib in plasma, with the method meeting all quantitative analysis requirements, including selectivity, accuracy, precision, stability, matrix effects, and recovery. In rat liver microsomes (RLM), tropifexor inhibited the metabolism of crizotinib via non-competitive and uncompetitive mechanisms, whereas in human liver microsomes (HLM), the inhibition occured through competitive and non-competitive mechanisms. In vivo studies in rats demonstrated that tropifexor significantly increased the AUC 0−t , AUC 0−∞ , and C max of crizotinib by 35.7%, 36.9%, and 37.5%, respectively, and decreased the CL z/F of crizotinib by 25.2%. For the metabolite 2-Keto crizotinib, tropifexor reduced its CL z/F by 27.9%. Our study developed this UPLC-MS/MS method for the accurate and sensitive quantitative determination of crizotinib and 2-Keto crizotinib concentrations, and elucidated the inhibitory effect of tropifexor on crizotinib metabolism and its inhibitory mechanism. The results of this study will support the necessity of monitoring crizotinib plasma concentrations when used in combination therapy.
Source: PeerJ
DOI: 10.7717/peerj.20256
Authors: An Shen, Hailun Xia, Jun Wu, Liang Tao, Jie Chen, HangJuan Lin
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,395
OpenAlex ID: W4415421003