title: Puerarin offsets the anticoagulation effect of warfarin in rats by inducing rCyps, upregulating vitamin K epoxide reductase and inhibiting thrombomodulin.
abstract: OBJECTIVE
  The current study was conducted to investigate the potential pharmacokinetic and pharmacodynamic interactions between warfarin and puerarin which is the most abundant component in Pueraria lobata (Gegen). In vivo and ex vivo rat models were used to reveal the underlying mechanisms of such interactions.
  
  
  METHODS
  Apart from one control group, five groups of Sprague-Dawley rats were treated with warfarin, oral puerarin, oral puerarin with warfarin, intravenous puerarin, intravenous puerarin with warfarin. The treatment lasted for 5 consecutive days. Thereafter, the levels of warfarin, warfarin metabolites and puerarin in plasma of these rats were monitored and compared. The rCyps activity and expression in rat livers of different treatment groups were assessed. The prothrombin time was observed. The vitamin K epoxide reductase (VKOR) activity and expression in rat livers were evaluated. Thrombomodulin activity and expression in the rat lung and rat plasma were assessed. The soluble thrombomodulin (sTM) concentrations of different treatment groups were examined.
  
  
  RESULTS
  Intravenously administered puerarin altered the pharmacokinetics of warfarin significantly by shortening t1/2, decreasing AUC0-96 hand increasing the clearance of warfarin. Further mechanistic studies suggested that both oral and intravenous administration of puerarin significantly induced the activities and expressions of rCyp2b1, rCyp2c6 and rCyp1a1. In addition, co-administration of puerarin reduced the prothrombin time of rat plasma by enhancing VKOR and inhibiting thrombomodulin.
  
  
  CONCLUSIONS
  Puerarin increased warfarin metabolism and offset warfarin anticoagulation by inducing rCyps, upregulating VKOR and inhibiting thrombomodulin in rats. The clinical impact of such potential interactions warrants further verification. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.|School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, SAR, Shatin, New Territories, Hong Kong.
authors.forename: Beikang
authors.initials: B
authors.lastname: Ge
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, SAR, Shatin, New Territories, Hong Kong.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, SAR, Shatin, New Territories, Hong Kong.
authors.forename: Teddy Taining
authors.initials: TT
authors.lastname: Lam
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, SAR, Shatin, New Territories, Hong Kong.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D007529:Isoflavones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011517:Prothrombin Time; D051381:Rats; D017207:Rats, Sprague-Dawley; D018180:Thrombomodulin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D064417:Vitamin K Epoxide Reductases / Q000235:genetics / Q000378:metabolism*; D014859:Warfarin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D002316:Cardiotonic Agents; D007529:Isoflavones; D018180:Thrombomodulin; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D064417:Vitamin K Epoxide Reductases; C033607:puerarin
keywords: liver cytochrome P450; puerarin; thrombomodulin; vitamin K epoxide reductase; warfarin