title: Influence of CYP3A5*3 and ABCB1 C3435T on clinical outcomes and trough plasma concentrations of imatinib in Nigerians with chronic myeloid leukaemia.
abstract: OBJECTIVE
  Imatinib mesylate is the first-line drug for the treatment of Philadelphia/bcr-abl positive chronic myeloid leukaemia (CML). It is known to be metabolized mostly by CYP3A4 and CYP3A5 isoforms while its efflux is mediated by the transporters ABCB1 and ABCG2. Genetic polymorphism of some of these enzymes and transporters have been linked with inter-individual variations in the pharmacokinetics of the drug. This study, therefore, investigated the influence of CYP3A5*3, ABCG2 421C>A and ABCB1 3435 C>T genetic polymorphism on the clinical outcome and steady-state trough plasma concentration (TPC) of imatinib in Nigerians with CML.
  
  
  METHODS
  A total of 110 Nigerians with CML each of whom had been receiving a 400 mg daily dose of imatinib for at least 1 month were genotyped for CYP3A5*3, ABCG2 421C>A and ABCB1 3435 C>T. The TPC of all the patients were determined by a validated HPLC method and possible relationships between genotypes, age, clinical outcome, sex, TPC and ethnicity were analysed.
  
  
  CONCLUSIONS
  Subjects of TT genotype of ABCB1 C3435T had higher frequencies of complete haematological response (CHR), complete cytogenetic response (CCR) and major molecular response (MMR) but these were not statistically significant (P < 0·05). No genetic polymorphism in ABCG2 421C>A was observed. However, significant associations were observed between TPC and various genotypes in both CYP3A5*3 (P < 0·001) and ABCB1 C3435T (P < 0·001). The GG and TT genotypes in CYP3A5*3 and ABCB1 C3435T, respectively, were linked with higher TPC.
  
  
  CONCLUSIONS
  This is the first pharmacogenetics study of CML patients in the Nigerian population with ethnic differences in the distribution of ABCB1 C3435T. Genetic polymorphisms in CYP3A5*3 and ABCB1 C3435T are associated with TPC in CML patients in this population.
authors.affiliation: Department of Pharmaceutical Chemistry, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: B A
authors.initials: BA
authors.lastname: Adeagbo
authors.affiliation: Department of Pharmaceutical Chemistry, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: O O
authors.initials: OO
authors.lastname: Bolaji
authors.affiliation: Department of Pharmaceutical Chemistry, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: T A
authors.initials: TA
authors.lastname: Olugbade
authors.affiliation: Department of Haematology & Immunology, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: M A
authors.initials: MA
authors.lastname: Durosinmi
authors.affiliation: Department of Haematology & Immunology, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: R A
authors.initials: RA
authors.lastname: Bolarinwa
authors.affiliation: African Institute of Biomedical Science and Technology, Harare, Zimbabwe.
authors.forename: C
authors.initials: C
authors.lastname: Masimirembwa
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000097:blood* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate / Q000097:blood* / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009549:Nigeria; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic / Q000235:genetics; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A
keywords: ABCB1 C3435T; CYP3A5*3; chronic myeloid leukaemia; genetic polymorphism; imatinib