title: Absorption properties and effects of caffeic acid phenethyl ester and its p-nitro-derivative on P-glycoprotein in Caco-2 cells and rats.
abstract: BACKGROUND
  Caffeic acid phenethyl ester (CAPE), isolated from honeybee propolis, has pharmacological applications. A synthesized CAPE derivative, p-nitro-caffeic acid phenethyl ester (CAPE-NO2), showed similar activities with CAPE. The pharmacological activities of CAPE and CAPE-NO2are related to their absorption properties.
  
  
  OBJECTIVE
  To understand the pharmacokinetic profiles of CAPE and CAPE-NO2in rats and investigate the absorption mechanisms and effects on P-glycoprotein in Caco-2 cells.
  
  
  METHODS
  The pharmacokinetic profiles of CAPE and CAPE-NO2were obtained after oral administration (10 mg/kg) to rats. Transport studies of CAPE and CAPE-NO2(5, 10, 20 μM) were performed in Caco-2 cell model. P-gp activities were assayed by rhodamine 123 cellular retention. Expression of P-gp was determined after the cells were administrated with CAPE and CAPE-NO2(5, 20 μM) for 48 and 72 h.
  
  
  RESULTS
  The AUC(0-t)of CAPE-NO2(3239.9 ± 352 ng × h/mL) was two-time greater than CAPE (1659.6 ± 152 ng × h/mL) in rats. The Pappvalues of CAPE and CAPE-NO2were (4.86 ± 0.90) × 10-6cm/s and (12.34 ± 1.6) × 10-6cm/s, respectively. The accumulation of rhodamine 123 was increased by 1.3- to 1.9-fold and 1.4- to 2.3-fold in CAPE and CAPE-NO2groups after 1 h administration, respectively. However, CAPE and CAPE-NO2increased the P-gp levels by 2.1- and 1.7-fold, respectively.
  
  
  CONCLUSIONS
  The absorption of CAPE-NO2can be enhanced in rats and Caco-2 cells compared with CAPE. The two compounds are potential inhibitors of P-gp. The increased P-gp levels generated by CAPE and CAPE-NO2played a role as a defense mechanism by limiting intracellular xenobiotic levels.
authors.affiliation: a College of Pharmaceutical Sciences , Southwest University , Chongqing , P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gou
authors.affiliation: a College of Pharmaceutical Sciences , Southwest University , Chongqing , P.R. China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Yao
authors.affiliation: a College of Pharmaceutical Sciences , Southwest University , Chongqing , P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Tang
authors.affiliation: a College of Pharmaceutical Sciences , Southwest University , Chongqing , P.R. China.
authors.forename: Kaili
authors.initials: K
authors.lastname: Zou
authors.affiliation: a College of Pharmaceutical Sciences , Southwest University , Chongqing , P.R. China.
authors.forename: Yujia
authors.initials: Y
authors.lastname: Liu
authors.affiliation: a College of Pharmaceutical Sciences , Southwest University , Chongqing , P.R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zuo
authors.affiliation: a College of Pharmaceutical Sciences , Southwest University , Chongqing , P.R. China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: a College of Pharmaceutical Sciences , Southwest University , Chongqing , P.R. China.
authors.forename: Zhubo
authors.initials: Z
authors.lastname: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D002109:Caffeic Acids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002109:Caffeic Acids; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol
keywords: P-gp; p-nitro caffeic acid phenethyl ester; pharmacokinetics; rhodamine 123; transport