title: Simultaneous determination of macitentan and its active metabolite in human plasma by liquid chromatography-tandem mass spectrometry.
abstract: Macitentan is a newly approved endothelin receptor antagonist (ERA) for the long-term treatment of PAH with superior receptor-binding properties and a longer duration of action compared to other available ERAs. However, analytical methods for simultaneous determination of macitentan and its active metabolite, ACT-132577, in human plasma have not been fully reported in the literature. In this work, a fast, sensitive, and reliable high-performance liquid chromatography-tandem mass spectrometry method (HPLC-MS/MS) was firstly developed and completely validated for simultaneous determination of macitentan and its active metabolite in human plasma. Plasma samples were processed with a protein precipitation using acetonitrile, followed by chromatographic separation using an Inertsil ODS-SP column (100×2.1mm, 3.5μm) under isocratic elution with a mobile phase consisting of acetonitrile and 0.2% formic acid at a flow rate of 0.3mL/min. Quantification was operated in multiple reaction monitoring (MRM) mode using the transitions m/z 547.1→201.0 for macitentan, m/z 589.0→203.0 for ACT-132577, and m/z 380.5→243.3 for the IS (donepezil). The assay exhibited a linear range of 1-500ng/mL for both macitentan and ACT-132577. The accuracy and the intra- and inter-precisions were within acceptable ranges and no significant matrix effect was observed during the method validation. The developed method was successfully utilized to a human pharmacokinetic study of macitentan as well as ACT-132577 after oral administration of 10mg macitentan tablet in healthy Chinese volunteers.
authors.affiliation: Institute of Clinical Pharmacy, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
authors.forename: Lixiu
authors.initials: L
authors.lastname: Yu
authors.affiliation: Institute of Clinical Pharmacy, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Institute of Clinical Pharmacy, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: He
authors.affiliation: Institute of Clinical Pharmacy, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
authors.forename: Huqun
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Infectious Disease, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China. Electronic address: shining_119@163.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Institute of Clinical Pharmacy, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China. Electronic address: wenzhang_sci@163.com.
authors.forename: Weiyong
authors.initials: W
authors.lastname: Li
mesh_terms: D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D006801:Humans; D057230:Limit of Detection; D011743:Pyrimidines / Q000097:blood* / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D013449:Sulfonamides / Q000097:blood* / Q000493:pharmacokinetics; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D011743:Pyrimidines; D013449:Sulfonamides; C533860:macitentan
keywords: HPLC–MS/MS; Human plasma; Macitentan; Metabolite; Pharmacokinetic