title: Correlation between imatinib trough concentration and efficacy in Chinese chronic myelocytic leukemia patients.
abstract: BACKGROUND
  Trough imatinib plasma concentration, intracellular drug levels and expression of drug transporters can be indicative of clinical responses in chronic myelocytic leukemia (CML) patients receiving imatinib. We aimed to determine plasma imatinib concentration, intracellular imatinib concentration, human organic cation transporter 1 (hOCT1) and adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) mRNA expression in bone marrow cells of CML patients in order to evaluate the potential usefulness of these measures as markers of imatinib efficacy and understand their clinical relationships.
  
  
  METHODS
  Eighty-four CML patients receiving imatinib treatment were included in this study. Imatinib trough concentration was determined by high-performance liquid chromatography-tandem mass spectrometry. Real-time quantitative PCR with a TaqMan probe was used to assess hOCT1 and ABCB1 mRNA expression in bone marrow cells. All patients were divided into the major molecular response (MMR), complete cytogenetic response (CCyR), partial cytogenetic response (PCyR) or drug-resistant groups according to their response.
  
  
  RESULTS
  The plasma imatinib trough concentration was significantly higher in the MMR group than in the PCyR (p = 0.002) or drug-resistant groups (p = 0.011). The plasma imatinib trough concentration was also significantly higher in the CCyR group than in the PCyR group (p = 0.027). There were no significant differences between the CCyR and MMR groups with regard to the plasma imatinib trough concentration (p = 0.136). The intracellular imatinib concentration in bone marrow cells was significantly higher in the CCyR group compared to the drug-resistant or PCyR groups (p = 0.013). The hOCT1 mRNA expression in bone marrow cells was significantly higher in the CCyR group than in the drug-resistant or PCyR groups (p = 0.036). The ABCB1 mRNA expression in bone marrow cells was significantly higher in the drug-resistant group than in the CCyR or PCyR groups (p = 0.013). Plasma imatinib trough concentration was positively correlated with α(1)-acid glycoprotein (r = 0.443, p < 0.001) or dose (r = 0.422, p < 0.001).
  
  
  CONCLUSIONS
  Clinical responses in CML patients are correlated with both the plasma trough concentrations and intracellular levels of imatinib.
authors.affiliation: Department of Haematology, Guangzhou Red Cross Hospital, China.
authors.forename: Jian-Sheng
authors.initials: JS
authors.lastname: Zhong
authors.forename: Fan-Yi
authors.initials: FY
authors.lastname: Meng
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Zhou
authors.forename: Min
authors.initials: M
authors.lastname: Dai
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000097:blood* / Q000627:therapeutic use*; D044466:Asian People; D001483:Base Sequence; D001549:Benzamides; D001854:Bone Marrow Cells / Q000378:metabolism; D002648:Child; D002681:China; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D027702:Organic Cation Transporter 1 / Q000235:genetics; D010879:Piperazines / Q000097:blood* / Q000627:therapeutic use*; D011743:Pyrimidines / Q000097:blood* / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D027702:Organic Cation Transporter 1; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate