title: Estimation of CYP2D6*10 genotypes on citalopram disposition in Chinese subjects by population pharmacokinetic assay.
abstract: OBJECTIVE
  There is great interindividual variability in citalopram (CIT) pharmacokinetics. We attempted to establish a population pharmacokinetic (PPK) model of CIT in Chinese healthy subjects, to evaluate the effect of genetic polymorphism on CIT pharmacokinetics and to compare the PPK and non-compartmental (NCA) assays in the estimation of CIT bioequivalence.
  
  
  METHODS
  Blood samples of 23 healthy subjects were collected after administration of CIT; plasma concentration of CIT was analysed using LC/MS-MS. CYP2C19 and CYP2D6*10 genotypes were determined. PPK model was established by using nonlinear mixed-effect modelling (NONMEM). The model was evaluated using goodness-of-fit plots and relative error measurements. Bioequivalence of CIT was evaluated by both PPK and NCA method.
  
  
  CONCLUSIONS
  The estimated population absorption rate constant (ka ), clearance (CL/F) and volume of distribution (Vd/F) in Chinese healthy subjects are 0.64 L/h, 12.7 L/h and 705 L, respectively. Different CYP2C19 and CYP2D6 genotypes have impacts on CIT pharmacokinetics. There is about 5.5% decrement of CL/F for each CYP2C19*2 or CYP2D6*10 allele. The 90% confidence interval of CIT bioavailability obtained from NCA and PPK model were 96.4-105.4% and 92.5-103.4%, respectively.
  
  
  CONCLUSIONS
  The PPK of CIT is best characterized by a one-compartment disposition model with first-order absorption. CYP2C19 and CYP2D6 genotypes have impacts on the CL/F of CIT. Bioequivalence of CIT can be estimated by both NCA and PPK model.
authors: Department of Pharmacy, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors: B
authors: B
authors: Chen
authors: Y
authors: Y
authors: Xu
authors: T
authors: T
authors: Jiang
authors: R
authors: R
authors: Feng
authors: J
authors: J
authors: Sun
authors: W
authors: W
authors: Zhang
authors: W
authors: W
authors: Yang
authors: J
authors: J
authors: Li
authors: O
authors: O
authors: Adeniyi
authors: H
authors: H
authors: Chen
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044466:Asian People; D002626:Chemistry, Pharmaceutical; D015283:Citalopram / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D015233:Models, Statistical; D011110:Polymorphism, Genetic / Q000235:genetics; D011153:Population; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D015283:Citalopram; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6
keywords: CYP2C19; CYP2D6; bioequivalence; citalopram; genotype; non-compartment; population pharmacokinetic