title: Mechanistic understanding of the effect of Dengzhan Shengmai capsule on the pharmacokinetics of clopidogrel in rats.
abstract: BACKGROUND
  The Dengzhan Shengmai capsule (DZSM) is known in China for its remarkable curative effect as a treatment of cardiovascular diseases, such as coronary heart disease and ischemic stroke. DZSM is a Chinese herbal compound preparation that consists of four ingredients, including Erigeron breviscapus (Vaniot) Hand.-Mazz., Panax ginseng C.A. Mey, Ophiopogon japonicas (Thunb.) Ker-Gawl. and Schisandra chinensis (Turcz.) Baill., and was indexed in the Chinese Pharmacopoeia 2010. DZSM and clopidogrel are often co-prescribed in the clinic to prevent the recurrence of stroke or other cardiovascular and cerebrovascular diseases. However, the effect of DZSM on the pharmacokinetics of clopidogrel remains unclear.
  
  
  OBJECTIVE
  The purpose of the study is to explore the pharmacokinetics and potential interaction between DZSM and clopidogrel and the underlying mechanism.
  
  
  METHODS
  Rats were used to investigate the effect of DZSM on the pharmacokinetics of clopidogrel and its active metabolite in vivo. The plasma concentrations were simultaneously determined using LC-MS/MS. The effects of DZSM on the P-gp-mediated efflux transport and CYP450-mediated metabolism of clopidogrel were investigated using MDCKII-MDR1 cells and rat liver microsomes, respectively.
  
  
  RESULTS
  After pretreatment with DZSM, the Cmaxand AUC0-∞of clopidogrel increased from 0.4±0.1 to 1.7±0.6ng/mL and 0.9±0.4 to 2.0±0.2ng/mLh, respectively. The Cmaxand AUC0-∞of the derivatized active metabolite of clopidogrel decreased from 8.2±1.2 to 2.8±0.5ng/mL and 18.2±5.6 to 6.4±3.7ngh/mL, respectively. In MDCKII-MDR1 cells, the P-gp-mediated efflux transport of clopidogrel was significantly inhibited by the DZSM extract. In rat liver microsomes, DZSM inhibited clopidogrel metabolism with an IC50of 0.02mg/mL.
  
  
  CONCLUSIONS
  DZSM significantly affects the pharmacokinetics of clopidogrel and its active metabolite by inhibiting the P-gp-mediated efflux transport and CYP450-mediated metabolism of clopidogrel. Thus, caution is needed when DZSM is co-administered with clopidogrel in the clinic because the interaction of these drugs may result in altered plasma concentrations of clopidogrel and its active metabolite.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Xinmeng
authors.initials: X
authors.lastname: Chen
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
authors.forename: Zhongxiang
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Yibei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Gou
authors.affiliation: Guangdong Provincial Hospital of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 111# Dade Road, Guangzhou 510120, PR China.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Zhong
authors.affiliation: Guangdong Provincial Hospital of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 111# Dade Road, Guangzhou 510120, PR China.
authors.forename: Yefeng
authors.initials: Y
authors.lastname: Cai
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China. Electronic address: jinjing@mail.sysu.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D065767:Activation, Metabolic; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000633:toxicity; D002853:Chromatography, Liquid; D000077144:Clopidogrel; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage* / Q000633:toxicity; D041743:Herb-Drug Interactions; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D053719:Tandem Mass Spectrometry; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D014162:Transfection
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002317:Cardiovascular Agents; D004365:Drugs, Chinese Herbal; D010975:Platelet Aggregation Inhibitors; C000618380:dengzhan shengmai capsule; D003577:Cytochrome P-450 Enzyme System; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: Clopidogrel; Dengzhan Shengmai capsule; Herb-drug interaction; Metabolism; P-glycoprotein