title: CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation.
abstract: BACKGROUND
  The immunosuppressive drug cyclosporine (INN, ciclosporin), whose pharmacokinetic characteristics vary greatly among individuals, is a substrate for cytochrome P450 (CYP) 3A and P-glycoprotein, the product of the multidrug resistance 1 (MDR1) gene. Some of the single nucleotide polymorphisms (SNPs) in these genes are associated with deficient protein expression and reduced in vivo activity. We postulated that, in renal transplant recipients, these SNPs could be associated with interindividual variations in cyclosporine pharmacokinetics.
  
  
  OBJECTIVE
  In 106 renal transplant patients, we evaluated retrospectively the effects of 4 MDR1 SNPs [T-129C, C1236T, G2677(T,A), and C3435T] and of the CYP3A5*1/*3 SNP on cyclosporine pharmacokinetic parameters and exposure indices.
  
  
  RESULTS
  The CYP3A5*1 allele was present in 8.5% of patients. The MDR1 C1236T, G2677(T,A), and C3435T SNPs were frequent (17.9%, 18.9%, and 33%, respectively, for the variant homozygous genotype) and exhibited incomplete linkage disequilibrium. None of the cyclosporine pharmacokinetic parameters were associated with the CYP3A5 genetic polymorphism. Patients with the wild-type genotype in MDR1 C1236T SNP had slightly but significantly lower dose-adjusted peak drug concentrations (-16%) (P <.02) and dose-adjusted area under the concentration-time curve (AUC) values over the first 4 hours (-14%) (P <.05) as compared with mutated allele carriers. Haplotype analysis including MDR1 C1236T, G2677(T,A), and C3435T SNPs showed no significant association between haplotypes and cyclosporine pharmacokinetics or systemic exposure, although there was a nonsignificant trend toward higher dose-adjusted AUC values over the first 4 hours and AUC over the 12-hour administration interval for the T-T-T haplotype.
  
  
  CONCLUSIONS
  The presence of the CYP3A5 SNP does not explain the high variability of cyclosporine pharmacokinetics in stable renal transplant patients. Despite the weak association found for the MDR1 C1236T SNP, MDR1 SNPs are unlikely to be useful for cyclosporine dose optimization in clinical practice.
authors.affiliation: Unité INSERM UMR S490, Centre Universitaire des Saints-Péres, Paris, France. Dany.Anglicheau@univ-paris5.fr
authors.forename: Dany
authors.initials: D
authors.lastname: Anglicheau
authors.forename: Eric
authors.initials: E
authors.lastname: Thervet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Etienne
authors.forename: Bruno
authors.initials: B
authors.lastname: Hurault De Ligny
authors.forename: Yannick
authors.initials: Y
authors.lastname: Le Meur
authors.forename: Guy
authors.initials: G
authors.lastname: Touchard
authors.forename: Matthias
authors.initials: M
authors.lastname: Büchler
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.forename: David
authors.initials: D
authors.lastname: Tregouet
authors.forename: Philippe
authors.initials: P
authors.lastname: Beaune
authors.forename: Ann
authors.initials: A
authors.lastname: Daly
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D005602:France; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012189:Retrospective Studies
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017931:DNA Primers; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A