title: The P450 oxidoreductase *28 SNP is associated with low initial tacrolimus exposure and increased dose requirements in CYP3A5-expressing renal recipients.
abstract: OBJECTIVE
  Recently a SNP of the gene encoding P450 oxidoreductase (POR*28; rs1057868C>T) has been associated with increased in vivo CYP3A activity using midazolam as a drug probe. Because tacrolimus is metabolized by CYP3A isoenzymes, this SNP might affect tacrolimus pharmacokinetics.
  
  
  METHODS
  To test this hypothesis we performed a study in a cohort of 298 de novo renal allograft recipients stratified according to CYP3A5 genotype, which has a known impact on tacrolimus pharmacokinetics.
  
  
  RESULTS
  We found that in CYP3A5 expressers (CYP3A5*1 allele carriers) receiving a standard loading dose of 0.2 mg/kg, POR*28T allele carriers had lower tacrolimus C₀ levels in the first days post-transplantation and reached target C₀ levels significantly later as compared with POR*28CC homozygous patients. The POR*28T allele carriers had significantly higher tacrolimus dose requirements throughout the first year. In CYP3A5 nonexpressers (CYP3A5*3/*3) the POR*28 SNP did not affect tacrolimus pharmacokinetics.
  
  
  CONCLUSIONS
  These data indicate that the POR*28 SNP is associated with additional increases in early tacrolimus dose-requirements in patients carrying a CYP3A5*1 allele.
authors.affiliation: Department of Nephrology & Renal Transplantation, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Hylke
authors.initials: H
authors.lastname: de Jonge
authors.forename: Christoph
authors.initials: C
authors.lastname: Metalidis
authors.forename: Maarten
authors.initials: M
authors.lastname: Naesens
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Dirk R J
authors.initials: DR
authors.lastname: Kuypers
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D009251:NADPH-Ferrihemoprotein Reductase; D016559:Tacrolimus