Determination of antimalarial compound, ARB-89 (7尾-hydroxy-artemisinin carbamate) in rat serum by UPLC/MS/MS and its application in pharmacokinetics

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• 作者：Deepthi Pabbisetty^a ; ^{deepti.bits@gmail.com} ; Anuradha Illendula^b ; ¹ ; K.M. Muraleedharan^b ; ² ; Amar G. Chittiboyina^b ; ^c ; John S. Williamson^b ; Mitchell A. Avery^b ; ^c ; ^d ; Bonnie A. Avery^b ; ^c
• 关键词：Artemisinin analogs ; UPLC/MS/MS ; Pharmacokinetics ; Antimalarial ; Rat serum ; Bioavailability
• 刊名：Journal of Chromatography B ; Analytical Technologies in the Biomedical and Life Sciences
• 出版年：2012
• 期刊代码：124_15700232
• 类别：ch
• 出版时间：15 March, 2012
• 卷：889-890
• 期：Complete
• 页码：123-129
• 文件大小：387 K

摘要

Among all the antimalarial agents, artemisinin and its semi synthetic family of analogs are the most potent antimalarials available for the treatment of Plasmodium falciparum infections. But these analogs have a few issues such as shorter half-lives and low oral bioavailability values. In order to overcome these inherent problems, novel artemisinin analogs were synthesized from 7尾-hydroxy artemisinin by the Department of Medicinal Chemistry, University of Mississippi using a new synthesis mechanism. Out of all the 7尾-hydroxy artemisinin analogs synthesized, 7尾-hydroxy artemisinin carbamate (ARB-89) was chosen as a lead compound because of its high in vitro and in vivo activity. In this manuscript, a sensitive and rapid ultra-performance liquid chromatography tandem mass spectrometry (UPLC/MS/MS) method was developed and validated for the quantification of ARB-89 in rat serum. The analysis was carried out on an Acquity鈩?UPLC BEH C₁₈ column (1.7 渭m, 2.1 mm 脳 50 mm) with a flow rate of 0.3 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer in positive electrospray ionization (ESI) mode. The selected mass-to-charge (m/z) ratio transitions used in the multiple reaction monitoring (MRM) for ARB-89 and artemisinin (internal standard) were m/z 778.4 > 253.4 and m/z 283.4 > 151.1 respectively. The calibration curve was linear from 1.00 ng/mL to 10.0 渭g/mL (r² = 0.999). A simple protein precipitation method was used for extraction. Moreover, the inter-day and intra-day precision values were found to be less than 15%. The recoveries of the method ranged from 94.0%to 96.7%at three concentrations. ARB-89 in rat serum was found to be stable at room temperature for 12 h. This method was successfully used to quantitate the novel antimalarial compound ARB-89 after intravenous and oral administration to rats.