title: Integrated pharmacokinetics of five protoberberine-type alkaloids in normal and insomnic rats after single and multiple oral administration of Jiao-Tai-Wan.
abstract: BACKGROUND
  Jiao-Tai-Wan (JTW), an important herbal formula consists of Rhizoma coptidis and Cortex cinnamomi powder, is a famous prescription which has been used for centuries to treat insomnia in Traditional Chinese Medicine. The purpose of this study is to compare the pharmacokinetic properties of five protoberberine-type alkaloids (i.e. berberine, palmatine, coptisine, epiberberine and jatrorrhizine), the main bioactive constituents in JTW, between normal and insomnic rats. We also investigate the differences between single-dose and multiple-dose pharmacokinetics of five protoberberine-type alkaloids.
  
  
  METHODS
  The insomnic rat models were induced by intraperitoneal injection of one-dose para-chlorophenylalanine acid (PCPA). Quantification of five protoberberine-type alkaloids in rat plasma was achieved by using a rapid LC-MS/MS method. Plasma samples were collected at different time points to construct pharmacokinetic profiles by plotting drug concentration versus time and estimate pharmacokinetic parameters. An unpaired Student׳s t test was used for comparisons with SPSS 17.0.
  
  
  RESULTS
  The five protoberberine-type alkaloids of single-dose normal groups had slow absorption and low bioavailability, as well as a delay of peak time. In the single-dose oral administration, the Cmax and Tmax of five ingredients in insomnic rats had significant differences compared with those of normal rats. In the multiple-dose oral administration, the pharmacokinetic parameters of five protoberberine-type alkaloids varied greatly in insomnic rats. In the normal rats, there were significant differences (P<0.05) in the principal pharmacokinetic parameters such as Cmax and Tmax between single-dose and multiple-dose oral administration. In the insomnic rats, the five ingredients of multiple-dose groups showed better absorption than the single-dose groups. Particularly, three peaks were observed in multiple-dose model group of plasma-concentration curves.
  
  
  CONCLUSIONS
  The pharmacokinetic behavior of five protoberberine-type alkaloids was described in this paper. In both normal groups and model groups, the pharmacokinetic behavior of multiple-dose had significant differences comparing with the single-dose; either single-dose or multiple-dose, the pharmacokinetic behavior of insomnic rats had significant differences comparing the normal rats. Multiple dosing may improve the absorption of JTW in insomnic rats, which will increase the bioavailability and bring into active role in therapeutical effect.
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, 232 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, China.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, 232 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Liu
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, 232 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Cai
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, 232 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, China.
authors.forename: Xiuman
authors.initials: X
authors.lastname: Sun
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, 232 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, China.
authors.forename: Waner
authors.initials: W
authors.lastname: Hou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Wai huan Road East, Guangzhou Higher Education Mega Center, Guangzhou 510006, China.
authors.forename: Peiting
authors.initials: P
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Wai huan Road East, Guangzhou Higher Education Mega Center, Guangzhou 510006, China. Electronic address: xiezy2074@yahoo.com.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Xie
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, 232 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, China. Electronic address: liaoqf2075@yahoo.com.
authors.forename: Qiongfeng
authors.initials: Q
authors.lastname: Liao
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001600:Berberine Alkaloids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D010134:Fenclonine / Q000008:administration & dosage; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D007319:Sleep Initiation and Maintenance Disorders / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D001600:Berberine Alkaloids; D004365:Drugs, Chinese Herbal; C587966:jiao tai wan; C009090:protoberberine; D010134:Fenclonine
keywords: Berberine; Insomnic rat; Jiao-Tai-Wan; Pharmacokinetics; Protoberberine-type alkaloids