title: Effect of the CYP2C19 genotype on the pharmacokinetics of icotinib in healthy male volunteers.
abstract: OBJECTIVE
  Icotinib hydrochloride {4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline hydrochloride}, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), was designed for the treatment of non-small cell lung cancer (NSCLC). In the present study, we investigated the influence of the CYP2C19*2 and CYP2C19*3 alleles on the pharmacokinetics of icotinib in healthy Chinese volunteers.
  
  
  METHODS
  In a single-dose pharmacokinetic study, 12 healthy Chinese volunteers received an oral dose of 600 mg of icotinib. Plasma was sampled for up to 72 h post-dose, followed by quantification of icotinib by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS-MS).
  
  
  RESULTS
  Five subjects genotyped as homozygous extensive metabolizers (CYP2C19*1/*1), 6 subjects genotyped as heterozygous extensive metabolizers (CYP2C19*1/*2 or CYP2C19*1/*3), and 1 subject genotyped as a poor metabolizer (CYP2C19*2/*3) and was withdrawn from the research because of urticaria. The mean icotinib AUC(0-∞) and C(max) (14.56 ±5.31 h mg/L and 2.32 ± 0.49 μg/mL) in homozygous EMs was 1.56 and 1.41-fold lower than that in heterozygous EMs (22.7 ± 6.11 and 3.28 ± 0.48, P = 0.046 and 0.047). The mean CL/F (44.18 ± 12.17 L/h) in homozygous EMs was 1.55-fold higher than that in heterozygous EMs (28.42 ± 9.23 L/h, P = 0.013).
  
  
  CONCLUSIONS
  The data showed that the pharmacokinetics of icotinib differ significantly between homozygous EMs and heterozygous EMs in CYP2C19.
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, 1 Shuai Fu Yuan, Dong Chen District, Beijing, 100730, China.
authors.forename: Can-Jun
authors.initials: CJ
authors.lastname: Ruan
authors.forename: Dong-Yang
authors.initials: DY
authors.lastname: Liu
authors.forename: Ji
authors.initials: J
authors.lastname: Jiang
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
mesh_terms: D000328:Adult; D000483:Alleles; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D043844:Crown Ethers / Q000097:blood / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19; D005838:Genotype; D006801:Humans; D008297:Male; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D043844:Crown Ethers; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C531470:icotinib; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19