title: In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia.
abstract: BACKGROUND
  Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML.
  
  
  METHODS
  Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry.
  
  
  RESULTS
  Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity.
  
  
  CONCLUSIONS
  The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.
authors.affiliation: *Division of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University; †Department of Hematology and Coagulation, Skåne University Hospital, Lund; ‡Department of Medical Sciences, Uppsala University and Department of Hematology, University Hospital; §Analytical Chemistry, Department of Chemistry-Biomedical Center and Science for Life Laboratory, Uppsala University; ¶Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm; ‖Department of Hematology, Linköping University Hospital; **Department of Internal Medicine, Motala Hospital; ††Department of Medicine, Ryhov County Hospital, Jönköping; ‡‡Department of Internal Medicine, Västervik Hospital; and §§Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Skoglund
authors.forename: Johan
authors.initials: J
authors.lastname: Richter
authors.forename: Ulla
authors.initials: U
authors.lastname: Olsson-Strömberg
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergquist
authors.forename: Warunika
authors.initials: W
authors.lastname: Aluthgedara
authors.forename: S J Kumari A
authors.initials: SJ
authors.lastname: Ubhayasekera
authors.forename: Svante
authors.initials: S
authors.lastname: Vikingsson
authors.forename: Anna
authors.initials: A
authors.lastname: Svedberg
authors.forename: Stina
authors.initials: S
authors.lastname: Söderlund
authors.forename: Anna
authors.initials: A
authors.lastname: Sandstedt
authors.forename: Anders
authors.initials: A
authors.lastname: Johnsson
authors.forename: Jesper
authors.initials: J
authors.lastname: Aagesen
authors.forename: Jonas
authors.initials: J
authors.lastname: Alsenhed
authors.forename: Staffan
authors.initials: S
authors.lastname: Hägg
authors.forename: Curt
authors.initials: C
authors.lastname: Peterson
authors.forename: Kourosh
authors.initials: K
authors.lastname: Lotfi
authors.forename: Henrik
authors.initials: H
authors.lastname: Gréen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002648:Child; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007527:Isoenzymes / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010879:Piperazines / Q000097:blood; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000097:blood; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C464561:CGP 74588; D007527:Isoenzymes; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D051544:Cytochrome P-450 CYP3A