title: The influence of CYP3A, PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients.
abstract: OBJECTIVE
  Tacrolimus (Tac) and cyclosporine (CsA) are mainly metabolized by CYP3A4 and CYP3A5. Several studies have demonstrated an association between the CYP3A5 genotype and Tac dose requirements. Recently, CYP3A4, PPARA, and POR gene variants have been shown to influence CYP3A metabolism. The present study investigated potential associations between CYP3A5*3, CYP3A4*22, PPARA c.209- 1003G>A and c.208+3819A>G, and POR*28 alleles and dose-adjusted concentrations (C/D) of Tac and CsA in 177 renal transplant patients early post-transplant.
  
  
  METHODS
  All patients (n=177) were genotyped for CYP3A4*22, CYP3A5*3, POR*28, PPARA c.209-1003G>A, and PPARA c.208+3819A>G using real-time polymerase chain reaction (PCR) and melting curve analysis with allelespecific hybridization probes or PCR restriction fragment length polymorphisms (RFLP) methods. Drug concentrations and administered doses were retrospectively collected from patient charts at Oslo University Hospital, Rikshospitalet, Norway. One steady-state concentration was collected for each patient.
  
  
  RESULTS
  We confirmed a significant impact of the CYP3A5*3 allele on Tac exposure. Patients with POR*28 and PPARA variant alleles demonstrated 15 % lower (P=0.04) and 19 % higher (P=0.01) Tac C0/D respectively. CsA C2/D was 53 % higher among CYP3A4*22 carriers (P=0.03).
  
  
  CONCLUSIONS
  The results support the use of pre-transplant CYP3A5 genotyping to improve initial dosing of Tac, and suggest that Tac dosing may be further individualized by additional POR and PPARA genotyping. Furthermore, initial CsA dosing may be improved by pre-transplant CYP3A4*22 determination.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Lunde
authors.forename: Sara
authors.initials: S
authors.lastname: Bremer
authors.forename: Karsten
authors.initials: K
authors.lastname: Midtvedt
authors.forename: Beata
authors.initials: B
authors.lastname: Mohebi
authors.forename: Miriam
authors.initials: M
authors.lastname: Dahl
authors.forename: Stein
authors.initials: S
authors.lastname: Bergan
authors.forename: Anders
authors.initials: A
authors.lastname: Åsberg
authors.forename: Hege
authors.initials: H
authors.lastname: Christensen
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D047493:PPAR alpha / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D047493:PPAR alpha; D016572:Cyclosporine; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D009251:NADPH-Ferrihemoprotein Reductase; D016559:Tacrolimus