title: Pharmacokinetics of cyclophosphamide enantiomers in patients with breast cancer.
abstract: OBJECTIVE
  Adjuvant chemotherapy with cyclophosphamide (CYC) is used for the treatment of breast cancer. CYC is used as a racemic mixture, although preclinical data have demonstrated differences in the efficacy and toxicity of its enantiomers, with (S)-(-)-CYC exhibiting a higher therapeutic index. The present study investigated the enantioselectivity and influence of CYP2B6, CYP2C9, CYP2C19, and CYP3A on the kinetic disposition of CYC in patients with breast cancer.
  
  
  METHODS
  Fifteen patients previously submitted to removal of the tumor and treated with racemic CYC (900 or 1,000 mg/m(2)) and epirubicin were included in the study. The in vivo activity of CYP3A was evaluated using midazolam as a marker drug. Serial blood samples were collected up to 24 h after administration of the first cycle of CYC.
  
  
  RESULTS
  The kinetic disposition of CYC was enantioselective in patients with breast cancer, with plasma accumulation of the (S)-(-)-CYC enantiomer (AUC 195.0 vs. 174.8 μg h/mL) due to the preferential clearance of the (R)-(+)CYC enantiomer (5.1 vs. 5.7 L/h). Clearance of either CYC enantiomer did not differ between the CYP2B6, CYP2C9, and CYP2C19 genotypes or as a function of the in vivo activity of CYP3A evaluated by midazolam clearance.
  
  
  CONCLUSIONS
  The pharmacokinetics of CYC is enantioselective in patients with breast cancer concomitantly treated with epirubicin and ondansetron. Genotyping or phenotyping did not contribute to adjustment of the CYC dose regimen in patients included in this study.
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto da Universidade de São Paulo, Avenida do Café s/n, Campus da USP, Ribeirão Preto, SP, 14040-903, Brazil.
authors.forename: Bruno José Dumêt
authors.initials: BJ
authors.lastname: Fernandes
authors.forename: Carolina de Miranda
authors.initials: Cde M
authors.lastname: Silva
authors.forename: Jurandyr Moreira
authors.initials: JM
authors.lastname: Andrade
authors.forename: Angelo do Carmo Silva
authors.initials: Ado C
authors.lastname: Matthes
authors.forename: Eduardo Barbosa
authors.initials: EB
authors.lastname: Coelho
authors.forename: Vera Lucia
authors.initials: VL
authors.lastname: Lanchote
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005838:Genotype; D006801:Humans; D008874:Midazolam / Q000493:pharmacokinetics; D008875:Middle Aged; D013237:Stereoisomerism
chemical_list: D015251:Epirubicin; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D008874:Midazolam