title: Influence of combined CYP3A4 and CYP3A5 single-nucleotide polymorphisms on tacrolimus exposure in kidney transplant recipients: a study according to the post-transplant phase.
abstract: OBJECTIVE
  The present study investigated in Tunisian renal transplant patients, genetic polymorphisms of CYP3A4 -392A>G and CYP3A5 6986A>G and their influence on tacrolimus (Tac) pharmacokinetics during early and late post-transplant (PT) phases and established customized ranges of Tac doses matching the C0 target levels according to CYP3A4 and CYP3A5 genotype combination and the PT phase.
  
  
  METHODS
  We included adult Tunisian patients having received Tac for de novo kidney grafts and undergone a therapeutic drug monitoring of Tac by morning C0 monitoring during early (1 to 90 days) and late (over 90 days) PT phases. The genomic DNA was extracted from peripheral blood mononuclear cells using a salting-out procedure. CYP3A4 promoter (rs2740574; -392A>G) and CYP3A5 (rs776746; 6986A>G) SNP genotyping was analyzed using PCR-RFLP.
  
  
  RESULTS
  Fifty-two patients were enrolled in the study. During the early PT phase, the CYP3A5 polymorphism but not that of CYP3A4, correlates significantly with Tac dose-normalized C0 (C0/D ratio). During the late PT phase, the effect of CYP3A4 polymorphism becomes significant and that of CYP3A5 becomes nonsignificant on Tac C0/D Tac. The mean daily doses (mg/kg) matching therapeutic C0, regardless of the CYP3A genotypes, were 0.16 ± 0.05 and 0.10 ± 0.05 during early and late PT phase, respectively. Carriers of the CYP3A4*1B allele require higher doses to maintain the C0 in the therapeutic range during the two PT phases. However, patients carrying the CYP3A5*1 require significant higher Tac doses, only during the early phase.
  
  
  CONCLUSIONS
  Our data support a critical role of the CYP3A5 6986A>G and CYP3A4 -392A>G polymorphisms on the variation of Tac exposure during the early and the late PT phase, respectively. The establishment of customized Tac doses, according to CYP3A4/CYP3A5 genotype combination and the PT time, may allow preventing graft rejection and improving the safety profile of this drug. Further studies are needed to investigate this issue.
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia.
authors.forename: Karim
authors.initials: K
authors.lastname: Aouam
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia.
authors.forename: Abdessalem
authors.initials: A
authors.lastname: Kolsi
authors.affiliation: Laboratory of Genetics, Faculty of Medicine, University of Monastir, Tunisia.
authors.forename: Emna
authors.initials: E
authors.lastname: Kerkeni
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia.
authors.forename: Nadia
authors.initials: N
authors.lastname: Ben Fredj
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia.
authors.forename: Amel
authors.initials: A
authors.lastname: Chaabane
authors.affiliation: Laboratory of Genetics, Faculty of Medicine, University of Monastir, Tunisia.
authors.forename: Kamel
authors.initials: K
authors.lastname: Monastiri
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Tunisia.
authors.forename: Naceur
authors.initials: N
authors.lastname: Boughattas
mesh_terms: D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: CYP3A4; CYP3A5; TDM; post-transplant time; southern Mediterranean; tacrolimus