title: Pharmacokinetics, brain distribution, release and blood-brain barrier transport of Shunaoxin pills.
abstract: BACKGROUND
  Shunaoxin pills, a traditional Chinese medicine (TCM) product, have been used to treat cerebrovascular diseases in China since 2005. The main active components of Shunaoxin pills are ferulic acid and ligustilide from Chuanxiong (Ligusticum chuanxiong Hort, Umbelliferae) and Danggui (Angelica sinensis radix, Umbelliferae). As Shunaoxin shows excellent activity in the central nervous system (CNS), the extent to which the major constituents of Shunaoxin reach the CNS should be investigated. Moreover, the in vivo-in vitro correlations (IVIVC) of the formulation should be studied to elucidate the mechanisms of action of TCM in the CNS. However, these data have not previously been available. Thus we intended to investigate what the extent when these constituents of Shunaoxin pills reach the CNS, and evaluate the IVIVC of release and pharmacokinetics.
  
  
  METHODS
  In this study, we evaluated the release of ferulic acid and ligustilide from Shunaoxin pills, and their transport across an in vitro model of the BBB. We also evaluated their pharmacokinetics and brain distribution in vivo. High-performance liquid chromatography (HPLC) was used to quantify both compounds simultaneously. Based on the release in vitro and absorption of ferulic acid and ligustilide in vivo, IVIVC permitted prediction of the pharmacokinetics of these compounds.
  
  
  RESULTS
  The release of ferulic acid and ligustilide reached a platform phase within 1h. Ferulic acid and ligustilide rapidly crossed the BBB in different patterns; the transport ratio increased over time. After intragastric (i.g.) administration of Shunaoxin pills, ferulic acid and ligustilide were rapidly absorbed and distributed into brain, which may result in a rapid onset of action.
  
  
  CONCLUSIONS
  Ferulic acid and ligustilide were transported across a model BBB. After i.g. administration of Shunaoxin pills, ferulic acid and ligustilide were rapidly absorbed and distributed in brain; this may lead to rapid pharmacological onset. The IVIVC can be used to predict in vivo pharmacokinetics from in vitro experimental results. These results provide support for the clinical use of Shunaoxin pills.
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wu
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Zhan-Zhang
authors.initials: ZZ
authors.lastname: Wang
authors.affiliation: Tianjin No. 6 Traditional Chinese Medicine Factory of Zhongxin Pharmaceuticals Group Co., Ltd. Tianjin 300401, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: qixr@bjmu.edu.cn.
authors.forename: Xian-Rong
authors.initials: XR
authors.lastname: Qi
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003373:Coumaric Acids / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D004285:Dogs; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013607:Tablets
chemical_list: D003373:Coumaric Acids; D004365:Drugs, Chinese Herbal; D013607:Tablets; C000591859:shunaoxin; C027820:ligustilide; C004999:ferulic acid; D015107:4-Butyrolactone
keywords: Blood–brain barrier; Ferulic acid; In vivo–in vitro correlation; Ligustilide; Pharmacokinetics; Shunaoxin pills