UPLC-MS/MS method for the determination of Lenvatinib in rat plasma and its application to drug-drug interaction studies

• Published in: Journal of pharmaceutical and biomedical analysis 2021-11, Vol.206, p.114360, Article 114360
• Main Authors: Cui, Yanjun, Li, Ying, Fan, Liju, An, Jing, Wang, Xiaonan, Fu, Ran, Dong, Zhanjun
• Format: Article
• Language: English
• Subjects: Animals; Carcinoma, Hepatocellular - drug therapy; Chromatography, High Pressure Liquid; Chromatography, Liquid; Drug Interactions; Drugs, Chinese Herbal - pharmacology; Drug–drug interaction; Lenvatinib; Liver Neoplasms - drug therapy; Pharmacokinetics; Phenylurea Compounds - pharmacology; Quinolines - pharmacology; Rats; Reproducibility of Results; Tandem Mass Spectrometry; UPLC-MS/MS; Wuzhi capsule
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2021.114360

•An UPLC-MS/MS method was developed for the determination of lenvatinib in rats.•The method was applied to evaluate the pharmacokinetics of lenvatinib in rats.•The effect of Wuzhi capsule on the pharmacokinetics of lenvatinib was evaluated.•Drug–drug interactions might exist between the two drugs. Lenvatinib (LEN) is a multitargeted tyrosine kinase inhibitor registered for the first-line treatment of unresectable advanced hepatocellular carcinoma. Wuzhi capsule (WZC) is a traditional Chinese medicine preparation; it is used to decrease the aminotransferase level of the liver and protect liver function. Thus, patients with hepatocellular carcinoma (HCC) are potentially treated with a combination of LEN and WZC, but there is no information about the interaction between the two drugs. We developed a simple, rapid, and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS) method for the quantitative determination of lenvatinib in rat plasma. Liquid–liquid extraction of plasma samples was carried out with ethyl acetate. Chromatographic separation of analyte was performed using gradient elution with acetonitrile and 0.1% formic acid water. The positive ion multi-response monitoring mode was used, and the target of the parent and daughter ions of LEN and IS were m/z 427.1→370 and m/z 432.1→370, respectively. All the validation projects were in accordance with the guidelines. Good linearity of 0.2–1000 ng/mL (r > 0.999) was achieved. The lower limit of quantification was 0.2 ng/mL. The precision and accuracy are acceptable. The method was successfully applied to pharmacokinetics and drug interaction analysis. The results show that WZC can significantly increase the Cmax (maximum plasma concentration) and AUC (area under the concentration-time curve) of LEN. An UPLC -MS/MS method that can be used for studying drug–drug interaction as a valuable tool was developed in this study. Drug-drug interactions were observed between the WZC and LEN.