title: Pharmacogenetics of tacrolimus after renal transplantation: analysis of polymorphisms in genes encoding 16 drug metabolizing enzymes.
abstract: BACKGROUND
  Tacrolimus (Tac) is an immunosuppressive drug used to prevent post-transplant (PT) organ rejection. Continuous Tac monitoring is necessary to adjust the dose and prevent toxicity or rejection. Tac is metabolized by cytochrome-P450 (CYP) enzymes, and variation at the CYP and other drug metabolizing enzymes could influence Tac bio-availability and dose requirements. Our aim was to define the effect of DNA variants at 16 drug metabolising enzymes on Tac dose in patients with kidney transplants.
  
  
  METHODS
  The REDINREN Pharmacogenetics Project was a multicenter study designed to evaluate the effect of DNA polymorphisms on Tac dose requirements. A total of 200 patients who received a first cadaveric kidney and Tac as primary immunosuppressive drug were genotyped for 96 DNA polymorphisms on 16 genes. Significant associations were further replicated in a second group of 200 patients. The Tac daily dose was adjusted to achieve a blood concentration of 10-15 ng/mL in the period 0-3 months PT, and 5-10 ng/mL thereafter. The dose of tacrolimus dose and blood concentrations were compared between genotypes at 1 week, 6 months, and 1 year PT.
  
  
  RESULTS
  The CYP3A5 genotype (SNP rs776746) was the strongest predictor of Tac dose requirements. Patients who were CYP3A5*3*3 (CYP3A5 non-expressors) received significantly higher Tac dose at 1 week, 6 months, and 1 year PT (p<0.0001). At 1 week, 41% of the CYP3A5 non-expressors achieved target blood concentrations compared to 26% of the CYP3A5 expressors (p=0.007). We also found a significant effect of CYP3A4 genotype (SNP rs2740574) on Tac dose requirements in patients who were CYP3A5 non-expressors. None of the other polymorphisms were related to Tac dose requirements or modified the effect of the CYP3A5 genotype.
  
  
  CONCLUSIONS
  rs776746 (CYP3A5) and rs2740574 (CYP3A4) were the only SNPs associated with Tac dosage. The genotyping of these polymorphisms could be a useful pharmacogenetic tool to determine the Tac dose immediately after transplantation.
authors.affiliation: Genética Molecular, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Tavira
authors.forename: Eliecer
authors.initials: E
authors.lastname: Coto
authors.forename: Eliecer Coto
authors.initials: EC
authors.lastname: Garciá
authors.forename: Carmen
authors.initials: C
authors.lastname: Díaz-Corte
authors.forename: Francisco
authors.initials: F
authors.lastname: Ortega
authors.forename: Manuel
authors.initials: M
authors.lastname: Arias
authors.forename: Armando
authors.initials: A
authors.lastname: Torres
authors.forename: Juan M
authors.initials: JM
authors.lastname: Díaz
authors.forename: Rafael
authors.initials: R
authors.lastname: Selgas
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Larrea
authors.forename: Josep M
authors.initials: JM
authors.lastname: Campistol
authors.forename: Victoria
authors.initials: V
authors.lastname: Alvarez
authors.forename: Victoria
authors.initials: V
authors.lastname: Alvarezca
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004247:DNA / Q000235:genetics; D023381:Endpoint Determination; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic / Q000235:genetics*; D057285:Precision Medicine; D015203:Reproducibility of Results; D016559:Tacrolimus / Q000378:metabolism*; D055815:Young Adult
chemical_list: D004798:Enzymes; D004247:DNA; D016559:Tacrolimus