title: Impact of CYP3A4*1B and CYP3A5*3 polymorphisms on the pharmacokinetics of cyclosporine and sirolimus in renal transplant recipients.
abstract: BACKGROUND
  Calcineurin inhibitor (cyclosporine, CsA) and mTOR inhibitors (sirolimus, SRL) - immunosuppressants used to prevent allograft rejection after renal transplantation - have a narrow therapeutic index and show considerable inter-individual pharmacokinetic differences. Differences in expression and activity of cytochrome P450 (CYP) 3A4 and 3A5 affect these pharmacokinetics; cytochrome activity differences are associated with CYP genetic polymorphisms.
  
  
  METHODS
  This study evaluated the effects of polymorphisms in CYP3A4 and CYP3A5 on immunosuppressive drug-dose adjusted trough blood concentrations. One hundred renal transplant recipients were genotyped for CYP3A4*1B and CYP3A5*3 using PCR-RFLP. Blood concentrations of CsA and SRL were determined by EMIT and HPLC/UV, respectively.
  
  
  RESULTS
  The allelic frequencies of CYP3A4*1B and CYP3A5*3 in the study group were 2.5% and 96.5%, respectively. The mean cyclosporine dose in CYP3A4*1/*1B subjects was 455.04±128.68 mg/day vs. 261.68±64.72 mg/day in CYP3A4*1/*1 subjects (p<0.001). The mean cyclosporine dose-adjusted trough blood concentrations (ng/ml per mg/kg body weight) in CYP3A4*1/*1B subjects were lower than in the CYP3A4*1/*1 group (37.06±10.38 vs. 44.63±13.99; p<0.218). The mean cyclosporine dose in CYP3A5*1/*3 subjects was 400.65±164.97 mg/day vs. 263.52±64.39 mg/day in CYP3A5*3/*3 subjects (p<0.022). No association was detected between sirolimus trough blood concentration (C0) or dose requirement, and CYP3A4 or CYP3A5 genotype.
  
  
  CONCLUSIONS
  Genetic polymorphisms in CYP3A4 and CYP3A5 may underlie inter-individual differences in cyclosporine pharmacokinetics after renal transplantation. Patients with at least 1 functional CYP3A5*1 or CYP3A4*1B allele require significantly higher doses of cyclosporine to reach target drug levels compared to patients with the CYP3A4*1 or CYP3A5*3 alleles.
authors.affiliation: Department of Immunology, Transplant Medicine and Internal Diseases, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland. d_zochowska@wp.pl
authors.forename: Dorota
authors.initials: D
authors.lastname: Żochowska
authors.forename: Janusz
authors.initials: J
authors.lastname: Wyzgał
authors.forename: Leszek
authors.initials: L
authors.lastname: Pączek
mesh_terms: D000328:Adult; D000483:Alleles; D016572:Cyclosporine / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006084:Graft Rejection / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007206:Individuality; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020123:Sirolimus / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D020123:Sirolimus