title: The effects of verapamil on the pharmacokinetics of curculigoside in rats.
abstract: BACKGROUND
  Clarifying the potential mechanism of the poor oral bioavailability of curculigoside would be helpful for for investigating pharmacological effects and clinical applications.
  
  
  OBJECTIVE
  To clarify the main mechanism for poor oral bioavailability.
  
  
  METHODS
  First, the pharmacokinetics of curculigoside (20 mg/kg) in rats with and without pretreatment with verapamil (10 mg/kg) was determined using a sensitive and reliable LC-MS method. Then the effects of verapamil on the transport and metabolic stability of curculigoside were investigated using Caco-2 cell transwell model and rat liver microsome incubation systems.
  
  
  RESULTS
  The results showed that verapamil could significantly increase the peak plasma concentration (from 60.17 ng/mL to 93.66 ng/mL) and AUC0-t(from 289.57 to 764.02 ng·h/mL) of curculigoside. The Caco-2 cell experiments indicated that the efflux ratio of curculigoside was 3.92 (PappAB6.43 ± 0.57 × 10-7cm/s; PappBA2.52 ± 0.37 × 10-36cm/s), P-gp might be involved in the transport of curculigoside, and verapamil could inhibit the efflux of curculigoside and increase the absorption of curculigoside significantly in the Caco-2 cell monolayer. Additionally, the rat liver microsome incubation experiments indicated that verapamil could significantly decrease the intrinsic clearance rate of curculigoside (from 38.8 to 23.6 μL/min/mg protein).
  
  
  CONCLUSIONS
  These results indicated that verapamil could significantly change the pharmacokinetic profiles of curculigoside in rats, the poor absorption due to P-gp mediated efflux in intestine and high intrinsic clearance rate in rat liver may be the main reason for the poor oral absolute bioavailability of curculigoside.
authors.affiliation: a Department of Orthopaedics , Qingdao Hiser Medical Group , Qingdao , Shandong , China.
authors.forename: Kaiyou
authors.initials: K
authors.lastname: Wang
authors.affiliation: a Department of Orthopaedics , Qingdao Hiser Medical Group , Qingdao , Shandong , China.
authors.forename: Jingming
authors.initials: J
authors.lastname: Zhao
authors.affiliation: a Department of Orthopaedics , Qingdao Hiser Medical Group , Qingdao , Shandong , China.
authors.forename: Jixiao
authors.initials: J
authors.lastname: Lang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D002853:Chromatography, Liquid / Q000379:methods; D004347:Drug Interactions / Q000502:physiology; D005960:Glucosides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D001565:Benzoates; D005960:Glucosides; C477170:curculigoside; D014700:Verapamil
keywords: CYP450; Caco-2 cells; P-gp; oral absolute bioavailability; verapamil