title: Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients.
abstract: OBJECTIVE
  The objective of this study was to retrospectively evaluate the effects of MDR1, CYP3A4*18B, and CYP3A5*3 genetic polymorphisms on cyclosporine A (CsA) pharmacokinetics in Chinese renal transplant patients during the first month after transplantation.
  
  
  METHODS
  A total of 103 renal transplant recipients receiving CsA were genotyped for MDR1 (C1236T, G2677T/A, and C3435T), CYP3A4*18B, and CYP3A5*3. The predose and 2-h postdose concentrations of CsA (C(0) and C(2), respectively) were determined by fluorescence polarization immunoassay, and their relationships with corresponding genotypes and haplotypes were investigated.
  
  
  RESULTS
  Patients with a CYP3A4*1/*1 genotype were found to have a higher dose-adjusted concentration compared with those with CYP3A4*18B/*18B, as follows: for C(2), 19.3% (P = 0.008) during days 8-15, 35.2% (P = 0.008) during days 16-30, and for C(0), 39.7% (P = 0.012) during days 16-30. The dose-adjusted C(0) was higher in patients with MDR1 1236CC compared with those with 1236TT in the first month postoperation. The dose-adjusted C(0) in patients with the CYP3A5*3/*3 genotype was 25.5% and 30.7% higher than those with the wild-type genotype during days 8-15 (P = 0.011) and days 16-30 (P = 0.015), respectively. Haplotype analysis revealed that the dose-adjusted C(0) was higher in the first month following surgery in carriers of haplotype MDR1 CAC than in noncarriers. Polymorphisms of MDR1 and CYP3A5*3 did not affect dose-adjusted C(2.)
  
  
  CONCLUSIONS
  The data suggests that the CYP3A4*18B genotype affects CsA pharmacokinetics during the first month following surgery in Chinese renal transplant recipients. Patients with CYP3A4*18B alleles may require higher doses of CsA to reach the target levels. Large prospective studies may be needed to further explore the impact of MDR1 and CYP3A5*3 polymorphisms on CsA pharmacokinetics in renal transplant recipients.
authors.affiliation: Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, 12 Wu Lu Mu Qi M. Rd, Shanghai 200040, People's Republic of China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Qiu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Jiao
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Long-Jin
authors.initials: LJ
authors.lastname: Zhong
authors.forename: Hui-Qi
authors.initials: HQ
authors.lastname: Liang
authors.forename: Chun-Lai
authors.initials: CL
authors.lastname: Ma
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Ming-Kang
authors.initials: MK
authors.lastname: Zhong
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D016572:Cyclosporine / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human