title: Influence of CYP3A4, CYP3A5 and MDR-1 polymorphisms on tacrolimus pharmacokinetics and early renal dysfunction in liver transplant recipients.
abstract: OBJECTIVE
  Tacrolimus is a widely used immunosuppressive drug in organ transplantation. The oral bioavailability of tacrolimus varies greatly between individuals and depends largely on the activity of both the cytochrome P450 3A (CYP3A) subfamily and P-glycoprotein (P-gp). The possible influence of single nucleotide polymorphisms (SNPs) of CYP3A subfamily and P-gp (MDR-1) in liver transplant recipients has recently been indicated as one of the most important variables affecting the pharmacokinetics of tacrolimus and the renal injury induced by tacrolimus.
  
  
  METHODS
  A total of 216 liver transplant recipients were enrolled in this study. The recipients' mean follow-up time was 52 mo (range from 16 to 96 mo). All liver transplant recipients were all in a stable stage with normal serum creatinine (SCr). All liver transplant recipients treated with tacrolimus were genotyped for CYP3A5 (6986A>G), CYP3A4 intron 6 (CYP3A4*22), MDR-1 exon 26 (3435C>T) and exon 12 (1236 C>T) SNPs by HRM analysis (high-resolution melting curve analysis). Recipients were defined as the early renal injury by the elevation of different microproteins in the urine including microalbumin (MA), urine immunoglobulin G (IGU), urine transferrin (TRU) and α1-microglobulin (A1M).
  
  
  RESULTS
  The daily dose of tacrolimus was higher for recipients with CYP3A5 1/1 (AA) genotype than those with CYP3A5 3/ 3 (GG) genotype [3.0 (2.0-4.0) versus 2.0 (1.5-2.5) mg/d, P<0.05]. The concentration/dose ratio of recipients with CYP3A5 1 homozygotes was lowest compared to recipients with CYP3A5 3/ 3 and CYP3A5 1/ 3 genotypes. Furthermore, the recipients carrying CYP3A5 3 allele were associated with increased risk of early renal glomerular injury compared to the recipients carrying CYP3A5 1 allele (P=0.01). MDR-1 polymorphisms were not related with tacrolimus pharmacokinetics and early renal injury.
  
  
  CONCLUSIONS
  CYP3A5 6986A>G genetic polymorphism affected daily dose requirements, concentration and nephrotoxicity of tacrolimus. Screening for this single nucleotide polymorphism before the transplantation might be helpful for the selection of adequate initial daily dose and to achieve the desired immunosuppression outcome.
authors.affiliation: Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Yunying
authors.initials: Y
authors.lastname: Shi
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Jiangtao
authors.initials: J
authors.lastname: Tang
authors.forename: Junlong
authors.initials: J
authors.lastname: Zhang
authors.forename: Yuangao
authors.initials: Y
authors.lastname: Zou
authors.forename: Bei
authors.initials: B
authors.lastname: Cai
authors.forename: Lanlan
authors.initials: L
authors.lastname: Wang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D014184:Transplantation, Homologous
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus