title: A pre-clinical pharmacokinetic study in rats of three naturally occurring iridoid glycosides, Picroside-I, II and III, using a validated simultaneous HPLC-MS/MS assay.
abstract: A selective and sensitive high-performance liquid chromatography-electro-spray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed for the simultaneous quantitative determination of Picroside-I, II, and III in rat plasma and tissue homogenate to aid the pre-clinical studies. The chromatographic separation was performed on a Hypersil GOLD AQ C18 column using a gradient elution program with a mobile phase consisting of 2mM ammonium acetate and acetonitrile. The detection was achieved using a triple quadrupole tandem MS in negative ionization multiple reaction monitoring (MRM) mode. One-step protein precipitation was selected for plasma and tissue sample preparation while liquid-liquid extraction failed to achieve satisfactory recoveries. The calibration curves of all three analytes in either plasma or tissue homogenate showed good linearity over the concentration range of 0.5-500ng/mL with a limit of quantitation at 0.5ng/mL. Both the intra- and inter-day accuracy and precision were within ±10%. The extraction recoveries were >70%, and the relative matrix effect ranged from 80.4% to 107.4% in all the biological samples. All the analytes were stable in matrices for at least 24h at room temperature, or 21 days in frozen. Three freeze/thaw cycles did not cause degradation. The method was successfully applied for quantification of the three iridoid glycosides in the collected plasma and various tissues following intravenous administration in rats. Picroside-I, II, and III were all eliminated rapidly with large volume of distribution. Among the three glycosides, Picroside-II showed the highest liver uptake, and only Picroside-I and II were found to get across the blood brain barrier (BBB). These results were consistent with their hepatoprotective or neuroprotective effects reported clinically. With the aid of the efficient and reliable simultaneous LC-ESI-MS/MS assay this pharmacokinetic study provided insights into their therapeutic targets of these three iridoid glycosides as well as valuable experimental basis for an expansion of their clinical indications.
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Pharmacy, Zheng Zhou University, Zheng Zhou 450000, People's Republic of China.
authors.forename: Bingyang
authors.initials: B
authors.lastname: Xue
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China. Electronic address: mabo19821221@163.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Ma
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China. Electronic address: nancyzhang03@hotmail.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Yao
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Qi
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China.
authors.forename: Yonglu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Life Science & Pharmaceutical Engineering, Nanjing Tech University, Nanjing 210009, People's Republic of China.
authors.forename: Hanjie
authors.initials: H
authors.lastname: Ying
authors.affiliation: School of Pharmacy, FMHS, The University of Auckland Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Zimei
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000825:Animal Structures / Q000737:chemistry; D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D002934:Cinnamates / Q000097:blood / Q000493:pharmacokinetics*; D004355:Drug Stability; D004365:Drugs, Chinese Herbal / Q000032:analysis / Q000493:pharmacokinetics*; D005260:Female; D057888:Iridoid Glucosides / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D032261:Picrorhiza / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D002934:Cinnamates; D004365:Drugs, Chinese Herbal; D057888:Iridoid Glucosides; C000604655:picroside-III; C109270:picroside I; C416837:picroside II
keywords: LC-MS/MS; Pharmacokinetics; Picroside-I; Picroside-II; Picroside-III; Simultaneous determination; Tissue distribution