title: Determination of antimalarial compound, ARB-89 (7β-hydroxy-artemisinin carbamate) in rat serum by UPLC/MS/MS and its application in pharmacokinetics.
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 C(18) column (1.7 μm, 2.1 mm × 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 μg/mL (r(2)=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.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, University of Mississippi, University, MS 38677, United States. deepti.bits@gmail.com
authors.forename: Deepthi
authors.initials: D
authors.lastname: Pabbisetty
authors.forename: Anuradha
authors.initials: A
authors.lastname: Illendula
authors.forename: K M
authors.initials: KM
authors.lastname: Muraleedharan
authors.forename: Amar G
authors.initials: AG
authors.lastname: Chittiboyina
authors.forename: John S
authors.initials: JS
authors.lastname: Williamson
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
authors.forename: Bonnie A
authors.initials: BA
authors.lastname: Avery
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D037621:Artemisinins / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D002219:Carbamates / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004355:Drug Stability; D016014:Linear Models; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: C519571:7-hydroxyartemisinin; D000962:Antimalarials; D037621:Artemisinins; D002219:Carbamates