title: Pharmacokinetic study of calenduloside E and its active metabolite oleanolic acid in beagle dog using liquid chromatography-tandem mass spectrometry.
abstract: Aralia mandshrica is a well-known traditional Chinese medicine from Northeast China commonly used to treat digestive, circulatory and immune system disorders. Calenduloside E is one of its bioactive components currently under evaluation as a pure drug. In this study, a highly sensitive and rapid method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the simultaneous quantitation of calenduloside E and its active metabolite oleanolic acid in beagle dog plasma has been developed and validated. Samples containing the ammonium salt of simvastatin acid as internal standard (IS) were purified by solid phase extraction and separated on a SUPELCO Ascentis-C18 column (50mm×4.6mm i.d., 5μm) using gradient elution with 0.35% formic acid and acetonitrile. Analytes and IS were detected in a cycle time of 5min after ionization in the negative ion mode by multiple reaction monitoring of the precursor-to-product ion transitions at m/z 631.4→455.4 and m/z 435.4→319.0 for calenduloside E and IS respectively and by single ion monitoring of the ion at m/z 455.4 for oleanolic acid. The method was linear over the concentration range 0.4-100ng/mL for both analytes using 0.5mL plasma. Inter- and intra-day precisions were both <6.96% with accuracies <6.40%. In the pharmacokinetic (PK) study, beagle dogs were given oral doses of calenduloside E (1.05, 2.10 and 4.20mg/kg) and an intravenous injection of 2.10mg/kg. The absolute bioavailability of calenduloside E was only 0.58%. Area under the plasma concentration time curve (AUC(0-t)) for the oral doses of calenduloside E was approximately dose proportional while other PK parameters (t1/2, Tmax and MRT) showed no significant differences among the three doses (P>0.05). The PK data provide a useful platform on which to base future clinical studies of calenduloside E.
authors.affiliation: Research Center for Drug Metabolism, College of Life Science, Jilin University, Changchun 130012, PR China; Clinical Pharmacology Center, Research Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, PR China.
authors.forename: Meiyun
authors.initials: M
authors.lastname: Shi
authors.affiliation: Research Center for Drug Metabolism, College of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Sciences, Jilin University, Changchun 130021, PR China.
authors.forename: Yantong
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Research Center for Drug Metabolism, College of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Longmei
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Research Center for Drug Metabolism, College of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Sen
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Academy of Chinese Medical Sciences of Jilin Province, Changchun 130021, PR China.
authors.forename: Huibo
authors.initials: H
authors.lastname: Xu
authors.affiliation: School of Pharmacy, University of Otago, PO Box 56, Dunedin, New Zealand.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Fawcett
authors.affiliation: Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, PR China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Sun
authors.affiliation: Research Center for Drug Metabolism, College of Life Science, Jilin University, Changchun 130012, PR China; Clinical Pharmacology Center, Research Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, PR China. Electronic address: gujk@mail.jlu.edu.cn.
authors.forename: Jingkai
authors.initials: J
authors.lastname: Gu
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods*; D004285:Dogs; D005260:Female; D016018:Least-Squares Analysis; D057230:Limit of Detection; D008297:Male; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D012503:Saponins / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D012503:Saponins; C543984:calenduloside E; D009828:Oleanolic Acid
keywords: Beagle dog; Calenduloside E; LC–MS/MS; Oleanolic acid; Pharmacokinetics