title: Association of CYP2C19*2 and associated haplotypes with lower norendoxifen concentrations in tamoxifen-treated Asian breast cancer patients.
abstract: The aim was to examine the influence of CYP2C19 variants and associated haplotypes on the disposition of tamoxifen and its metabolites, particularly norendoxifen (NorEND), in Asian patients with breast cancer.
  
  
  
  Sixty-six CYP2C19 polymorphisms were identified in healthy Asians (n = 240), of which 14 were found to be tightly linked with CYP2C19*2, CYP2C19*3 and CYP2C19*17. These 17 SNPs were further genotyped in Asian breast cancer patients receiving tamoxifen (n = 201). Steady-state concentrations of tamoxifen and its metabolites were quantified using liquid chromatography–mass spectrometry. Non-parametric tests and regression methods were implemented to evaluate genotypic–phenotypic associations and haplotypic effects of the SNPs.
  
  
  
  CYP2C19 functional polymorphisms and their linked SNPs were not significantly associated with plasma concentrations of tamoxifen and its main metabolites N-desmethyltamoxifen, (Z)-4-hydroxytamoxifen and (Z)-Endoxifen. However, CYP2C19*2 and its seven linked SNPs were significantly associated with lower NorEND concentrations, MRNorEND/NDDM and MRNorEND/(Z)-END. Specifically, patients carrying the CYP2C19*2 variant allele A had significantly lower NorEND concentrations [median (range), GG vs. GA vs. AA: 1.51 (0.38–3.28) vs. 1.28 (0.30–3.36) vs. 1.15 ng ml−1 (0.26–2.45, P = 0.010)] as well as significantly lower MRNorEND/(Z)-END [GG vs. GA vs. AA: 9.40 (3.27–28.35) vs. 8.15 (2.67–18.9) vs. 6.06 (4.47–14.6), P < 0.0001] and MRNorEND/NDDM [GG vs. GA vs. AA: 2.75 (0.62–6.26) vs. 2.43 (0.96–4.18) vs. 1.75 (1.10–2.49), P < 0.00001]. CYP2C19 H2 haplotype, which included CYP2C19*2, was also significantly associated with lower NorEND concentrations (P = 0.0020), MRNorEND/NDDM (P < 0.0001) and MRNorEND/(Z)-END (P < 0.0001), indicating significantly lower formation rates of NorEND.
  
  
  
  These data highlight the potential relevance of CYP2C19 pharmacogenetics in influencing NorEND concentrations in tamoxifen-treated patients, which may influence treatment outcomes.
authors.affiliation: Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: Joanne Siok Liu
authors.initials: JS
authors.lastname: Lim
authors.affiliation: Clinical Pharmacology, SingHealth, Singapore.
authors.forename: Natalia
authors.initials: N
authors.lastname: Sutiman
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University Tubingen, Germany.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Muerdter
authors.affiliation: Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: Onkar
authors.initials: O
authors.lastname: Singh
authors.affiliation: Center for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore.|Department of International Health, University of Tampere, Finland.
authors.forename: Yin Bun
authors.initials: YB
authors.lastname: Cheung
authors.affiliation: Division of Medical Oncology, National Cancer Centre, Singapore.
authors.forename: Raymond Chee Hui
authors.initials: RC
authors.lastname: Ng
authors.affiliation: Division of Medical Oncology, National Cancer Centre, Singapore.
authors.forename: Yoon Sim
authors.initials: YS
authors.lastname: Yap
authors.affiliation: OncoCare Cancer Centre, Mount Elizabeth Novena Medical Centre, Singapore.
authors.forename: Nan Soon
authors.initials: NS
authors.lastname: Wong
authors.affiliation: OncoCare Cancer Centre, Mount Elizabeth Novena Medical Centre, Singapore.
authors.forename: Peter Cher Siang
authors.initials: PC
authors.lastname: Ang
authors.affiliation: Division of Medical Oncology, National Cancer Centre, Singapore.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dent
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University Tubingen, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Schroth
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and Department of Clinical Pharmacology, University Hospital, Tubingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.|Clinical Pharmacology, SingHealth, Singapore.|Office of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Balram
authors.initials: B
authors.lastname: Chowbay
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D044466:Asian People; D001711:Biotransformation; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D064368:Healthy Volunteers; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D018931:Antineoplastic Agents, Hormonal; C574385:N,N-didesmethyl-4-hydroxytamoxifen; D013629:Tamoxifen; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6
keywords: Asians; CYP2C19; norendoxifen; pharmacogenetics; polymorphisms; tamoxifen