title: CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity.
abstract: OBJECTIVE
  Imatinib is currently used for the treatment of chronic myeloid leukemia (CML). The main metabolite CGP74588 has similar potency to that of imatinib and is a product of CYP3A4 and CYP3A5 metabolism. However, the clinical significance of the metabolism on therapeutic response and pharmacokinetics is still unclear. We designed this study to investigate the role of the CYP3A activity in the response to imatinib therapy.
  
  
  METHODS
  Fourteen CML patients were phenotyped for in vivo CYP3A activity using quinine as a probe drug. The plasma concentration ratio of quinine and its CYP3A metabolite was used for assessing CYP3A activity. The patients were divided into complete molecular responders with undetectable levels of BCR-ABL transcripts after 12 months of therapy and into partial molecular responders who had failed to achieve a complete molecular response.
  
  
  RESULTS
  Patients that achieved complete molecular response showed significantly (Mann-Whitney U-test, p=0.013) higher in vivo CYP3A activity (median quinine metabolic ratio = 10.1) than patients achieving partial molecular response (median = 15.9).
  
  
  CONCLUSIONS
  These results indicate a clinical significance of the CYP3A activity and its metabolic products in CML patients treated with imatinib.
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Gréen
authors.forename: Karin
authors.initials: K
authors.lastname: Skoglund
authors.forename: Franz
authors.initials: F
authors.lastname: Rommel
authors.forename: Rajaa A
authors.initials: RA
authors.lastname: Mirghani
authors.forename: Kourosh
authors.initials: K
authors.lastname: Lotfi
mesh_terms: D001549:Benzamides; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D010865:Pilot Projects; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012074:Remission Induction
chemical_list: D001549:Benzamides; C464561:CGP 74588; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016044:Fusion Proteins, bcr-abl