title: Influence of CYP2D6 and CYP3A4 Phenotypes, Drug Interactions, and Vitamin D Status on Tamoxifen Biotransformation.
abstract: OBJECTIVE
  In view of the large variability on therapeutic response and the multiple factors associated to tamoxifen (TAM) metabolic activation, this study aimed to evaluate the effect of CYP2D6 and CYP3A4 phenotypes, drug interactions, and vitamin D exposure on TAM metabolism in a group of breast cancer patients.
  
  
  METHODS
  Trough blood samples were collected from 116 patients. TAM and metabolites endoxifen (EDF), N-desmethyltamoxifen, and 4-hydroxytamoxifen (HTF) were measured in plasma by liquid chromatography-tandem mass spectrometry. CYP2D6 and CYP3A4 phenotyping were obtained according to [dextromethorphan]/[dextrorphan] and [omeprazole]/[omeprazole sulfone] metabolic ratios, measured by high-performance liquid chromatography in plasma collected 3 hours after oral administration of 33 mg of dextromethorphan and 20 mg of omeprazole. Vitamin D3 was measured in plasma by high-performance liquid chromatography-ultraviolet. Data on concomitant use of drug considered as CYP2D6 and CYP3A4 inhibitor or inducer and vitamin D supplementation were recorded.
  
  
  RESULTS
  About 20% of patients had reduced CYP2D6 metabolic activity and 7% CYP3A4 impaired metabolism. EDF levels diminished proportionally to the reduction of CYP2D6 metabolic activity (poor metabolizer 2.79 ng·mL, intermediate metabolizer (IM) 5.36 ng·mL, and extensive metabolizer 10.65 ng·mL, P < 0.01). Median plasma levels of TAM (161.50 ng·mL) and HTF (1.32 ng·mL) in CYP2D6 IM/CYP3A4 poor metabolizer patients were higher (P < 0.05) than those from CYP2D6 IM/CYP3A4 extensive metabolizer patients (122.07 ng·mL and 0.61 ng·mL, respectively). Seasons contributed to the interpatient variability of EDF and HTF levels; summer concentrations were 24% and 42% higher compared with winter. Vitamin D3 was not associated to CYP3A4 metabolic activity, indicating that other mechanisms might be involved in the relation between TAM metabolism and vitamin D exposure.
  
  
  CONCLUSIONS
  CYP3A4 contributes to the bioactivation of TAM through formation of HTF and becomes increasingly important in case of reduced or absent CYP2D6 activity. EDF and HTF exposure were associated to seasonal variations, with considerable higher plasma concentrations during summer.
authors: *Pós-graduação em Ciências Médicas, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre; †Instituto de Ciências da Saúde, Universidade Feevale, Novo Hamburgo; ‡Hospital de Clínicas de Porto Alegre; §Hospital Moinhos de Vento, Porto Alegre, Brazil; and ¶Louvain Centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
authors: Marina V
authors: MV
authors: Antunes
authors: Tatiana Aparecida da Fontoura
authors: TA
authors: Timm
authors: Vanessa
authors: V
authors: de Oliveira
authors: Dilana E
authors: DE
authors: Staudt
authors: Suziane
authors: S
authors: Raymundo
authors: Gustavo
authors: G
authors: Gössling
authors: Jorge V
authors: JV
authors: Biazús
authors: José A
authors: JA
authors: Cavalheiro
authors: Daniela D
authors: DD
authors: Rosa
authors: Pierre
authors: P
authors: Wallemacq
authors: Vincent
authors: V
authors: Haufroid
authors: Rafael
authors: R
authors: Linden
authors: Gilberto
authors: G
authors: Schwartsmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D013629:Tamoxifen / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry / Q000379:methods; D014807:Vitamin D / Q000097:blood
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D014807:Vitamin D; C016601:afimoxifene; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C028787:N-desmethyltamoxifen