Drug Design, Development and Therapy (May 2021)
Development of UPLC-MS/MS Method for Studying the Pharmacokinetic Interaction Between Dasatinib and Posaconazole in Rats
Abstract
Suili Yang,1,* Xiaoshan Zhang,2,3,* Yuzhen Wang,2,3 Congcong Wen,4 Chenxiang Wang,3 Ziye Zhou,5 Guanyang Lin3 1Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2College of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 4Laboratory Animal Center, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 5Clinical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guanyang Lin; Ziye ZhouDepartment of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou City, 325000, People’s Republic of ChinaTel +86-577-55579706Email [email protected]; [email protected] and Aim: Dasatinib is approved for the treatment of leukaemia worldwide. Triazole agents such as posaconazole may be used for the control of secondary fungal infection with leukaemia. This work aimed to develop a bioanalytical method to study the potential interaction between dasatinib and posaconazole.Methods: An ultrahigh-performance liquid chromatography-tandem mass spectrometry method was established to measure the plasma concentrations of dasatinib and posaconazole in rats simultaneously. Simple protein precipitation with acetonitrile was applied to extract dasatinib and posaconazole in samples. The chromatographic separation of analytes was conducted on an UPLC BEH C18 column using a mobile phase consisting of 0.1% aqueous formic acid and acetonitrile. Dasatinib and posaconazole were monitored in positive ion mode with the following mass transition pairs: m/z 488.2→ 401.1 for dasatinib and m/z 701.3→ 683.4 for posaconazole. The method was successfully applied for pharmacokinetic interaction between dasatinib and posaconazole.Results: The established method expressed good linearity in 1– 1000 ng/mL of dasatinib and 5– 5000 ng/mL of posaconazole, with limit of detection was 1 ng/mL and 5 ng/mL, respectively. Methodology validations, including accuracy, precision, matrix effect, recovery, and stability, met the US Food and Drug Administration (FDA) acceptance criteria for bioanalytical method validation. Dasatinib strongly inhibited the clearance of posaconazole in vivo, while posaconazole expressed no significant effect on the pharmacokinetics of dasatinib.Conclusion: Dasatinib alters the pharmacokinetics of posaconazole. Attention should be paid to the unexpected risk of adverse clinical outcomes when posaconazole is co-administered with dasatinib.Keywords: dasatinib, posaconazole, UPLC-MS/MS, interaction, pharmacokinetics
