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

Author:
Pabbisetty, Deepthi, Illendula, Anuradha, Muraleedharan, K.M., Chittiboyina, Amar G., Williamson, John S., Avery, Mitchell A., Avery, Bonnie A.
Source:
Journal of chromatography 2012 v.889-890 pp. 123-129
ISSN:
1570-0232
Subject:
Plasmodium falciparum, ambient temperature, artemisinin, bioavailability, blood serum, half life, intravenous injection, ionization, monitoring, oral administration, pharmacokinetics, rats, spectrometers, tandem mass spectrometry, ultra-performance liquid chromatography, Mississippi
Abstract:
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 7β-hydroxy artemisinin by the Department of Medicinal Chemistry, University of Mississippi using a new synthesis mechanism. Out of all the 7β-hydroxy artemisinin analogs synthesized, 7β-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™ UPLC BEH C₁₈ column (1.7μm, 2.1mm×50mm) with a flow rate of 0.3mL/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 1.00ng/mL to 10.0μg/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 12h. This method was successfully used to quantitate the novel antimalarial compound ARB-89 after intravenous and oral administration to rats.
Agid:
1004012