title: Impact of currently prescribed lipid-lowering drugs on plasma PCSK9 concentration: single or in combination study in rats.
abstract: BACKGROUND
  An emerging data suggested a significant impact of statins on PCSK9 concentration, while the rapid impacts of other lipid-lowering drugs such as ezetimibe and xuezhikang alone or in combination on PCSK9 and lipid profile have not been assessed. This study aims to investigate whether an enhanced PCSK9 concentration by single or combined therapy of lipid-lowering drugs currently used precedes the changes of lipid profile in rats.
  
  
  METHODS
  Sixty-three rats were randomly divided into six groups and orally administrated with placebo (N = 13), ezetimibe 10 mg/kg daily, Xuezhikang 1200 mg/kg daily, ezetimibe 10 mg/kg plus Xuezhikang 1200 mg/kg daily, pitavastatin 10 mg/kg daily or pitavastatin 10 mg/kg plus ezetimibe 10 mg/kg daily for 3 days (N = 10 for each group respectively). Blood samples were obtained at day 3 after orally administration. Plasma PCSK9 levels were determined by ELISA and lipid profile were measured by enzymatic assay.
  
  
  RESULTS
  Ezetimibe, Xuezhikang and pitavastatin alone and Xuezhikang plus ezetimibe as well as pitavastatin plus ezetimibe increased PCSK9 levels by 124%, 56%, 111%, 63% and 204% respectively (p < 0.05 compared with placebo). However, Xuezhikang plus ezetimibe did not enhance greater PCSK9 levels compared to monotherapy. Ezetimibe and pitavastatin in combination induced higher PCSK9 levels than pitavastatin monotherapy or co-therapy with ezetimibe plus Xuezhikang. There was no significant difference between any groups with regard to lipid profile levels at day 3 (P > 0.05).
  
  
  CONCLUSIONS
  Elevated PCSK9 concentration by ezetimibe, Xuezhikang and pitavastatin alone or in combination was found prior to the alterations of lipid profile in rats. Combination of Xuezhikang and ezetimibe significantly attenuated increase in PCSK9 compared to ezetimibe plus pitavastatin, suggesting that the former combination may be better than the latter in future clinical application.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.forename: Rui-Xia
authors.initials: RX
authors.lastname: Xu
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China. lijianjun938@yahoo.com.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Li
mesh_terms: D000818:Animals; D001384:Azetidines / Q000494:pharmacology* / Q000627:therapeutic use; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D000069438:Ezetimibe; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D000071449:Proprotein Convertase 9; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000097:blood*
chemical_list: D001384:Azetidines; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; C496822:xuezhikang; C510804:PCSK9 protein, rat; D000071449:Proprotein Convertase 9; D012697:Serine Endopeptidases; D000069438:Ezetimibe; C108475:pitavastatin