title: CYP3A4/5 polymorphisms affect the blood level of cyclosporine and tacrolimus in Chinese renal transplant recipients.
abstract: OBJECTIVE
  Both cyclosporine and tacrolimus display a narrow therapeutic index as well as high interindividual pharmacokinetic variability. We approached the effect of the CYP3A4*18B and CYP3A5*3 polymorphisms and haplotypes on the whole blood cyclosporine or tacrolimus concentration in Chinese renal transplant patients during the first month after transplantation.
  
  
  METHODS
  A total of 83 recipients receiving tacrolimus or cyclosporine was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The whole blood concentration was measured by enzyme-multiplied immunoassay technique.
  
  
  RESULTS
  Both CYP3A4*18B and CYP3A5*3 polymorphisms affected the tacrolimus dose-adjusted trough concentration (C0/D). The tacrolimus C0/D was higher in carriers of haplotype GG compared with the non-carriers. The cyclosporine dose-adjusted 2-hour post-dose concentrations (C2/D), dose-adjusted C0 + C2 ((C0 + C2)/D) and C2/C0 during Days 15 - 21 displayed significant difference among the three genotypes. Statistical difference was observed between CYP3A4*1/*1 and CYP3A4*18B/*18B groups and between CYP3A4*1/*18B and CYP3A4*18B/*18B groups, but no difference was detected between CYP3A4*1/*1 and CYP3A4*1/*18B groups. No difference was found in C0/D among the three genotypes of CYP3A4*18B polymorphism, and neither CYP3A5*3 polymorphisms nor CYP3A haplotype-derived genotypes affected the cyclosporine dose-adjusted concentration.
  
  
  CONCLUSIONS
  Genetic polymorphisms of CYP3A5*3 and CYP3A4*18B may be partly responsible in large interindividual variability of cyclosporine and tacrolimus blood levels in Chinese renal transplant patients during the first month after transplantation. A patient carried combined genotype of CYP3A4*1/*1-CYP3A5* 3/*3 might require lower tacrolimus doses to achieve target concentration levels. Genotyping of CYP3A4*18B and CYP3A5*3 before transplantation is of benefit in determining a suitable initial dose for each patient.
authors.affiliation: Pharmacy Department, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China.
authors.forename: Dan-ying
authors.initials: DY
authors.lastname: Li
authors.forename: Rui-chen
authors.initials: RC
authors.lastname: Teng
authors.forename: Huai-jun
authors.initials: HJ
authors.lastname: Zhu
authors.forename: Yun
authors.initials: Y
authors.lastname: Fang
mesh_terms: D000328:Adult; D002681:China; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood*; D016030:Kidney Transplantation; D008297:Male; D012150:Polymorphism, Restriction Fragment Length; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D004247:DNA; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus