title: The effect of CYP3A5 polymorphisms on the pharmacokinetics of tacrolimus in adolescent kidney transplant recipients.
abstract: BACKGROUND
  CYP3A5 gene polymorphism has been shown to influence tacrolimus (TAC) blood concentration and dose requirement in adult kidney transplant patients. The aim was to analyze retrospectively the modification induced by CYP3A5 gene polymorphism on TAC's pharmacokinetic parameters obtained from 26 adolescents receiving TAC as their main immunosuppressive drug.
  
  
  METHODS
  The adolescent kidney transplant patients were genotyped for CYP3A5*3 and grouped accordingly. TAC dose, blood levels, and dose-normalized TAC blood concentration and volume of distribution obtained at different post-transplant periods during the first post-transplant year were correlated with the corresponding genotype.
  
  
  RESULTS
  During the first three months post-transplant, heterozygotes (CYP3A5*1/*3) displayed a lower TAC blood concentration than homozygotes (CYP3A5*3/*3) (at 1 month: 7.8+/-2.1 vs. 13.4+/-6 ng/ml, p=0.007) despite a therapeutic monitoring strategy. Between 3-12 months post-transplant, TAC blood concentration was comparable between the two groups, but a two-fold increase in the daily drug dose was necessary for the heterozygotes (at 6 months: 0.23+/-0.1 vs. 0.13+/-0.06 mg/kg, p=0.04). The dose-normalized TAC concentration [(ng/ml)/(mg/kg)] was significantly lower in patients displaying the CYP3A5*1/*3 polymorphism (at 2 weeks: 33+/-2.16 vs. 71.1+/-37.8, p=0.01; 6 months: 35.4+/-12.9 vs. 85.2+/-58.9, p=0.01). At the same time, the volume of distribution of the drug in the latter group was distinctly increased for the entire post-transplant year (at 6 months: 1.79+/-0.42 vs. 0.73+/-0.5 l/kg, p=0.001).
  
  
  CONCLUSIONS
  The great influence of CYP3A5 on the pharmacokinetics and pharmacodynamics of TAC in young transplant recipients suggests the need for pre-transplant screening of this polymorphism to improve TAC therapy.
authors.affiliation: Laboratory of Clinical Pathology, Maggiore Hospital Policlinico, Mangiagalli and Regina Elena Foundation, IRCCS, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Tirelli
authors.forename: Mariano
authors.initials: M
authors.lastname: Ferraresso
authors.forename: Luciana
authors.initials: L
authors.lastname: Ghio
authors.forename: Elisa
authors.initials: E
authors.lastname: Meregalli
authors.forename: Valentina
authors.initials: V
authors.lastname: Martina
authors.forename: Mirco
authors.initials: M
authors.lastname: Belingheri
authors.forename: Camilla
authors.initials: C
authors.lastname: Mattiello
authors.forename: Emilio
authors.initials: E
authors.lastname: Torresani
authors.forename: Alberto
authors.initials: A
authors.lastname: Edefonti
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007668:Kidney / Q000187:drug effects*; D016030:Kidney Transplantation / Q000379:methods*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus