Effect of CYP3A5, CYP3A4, and ABCB1 genotypes as determinants of tacrolimus dose and clinical outcomes after heart transplantation

Transplant Proc. 2012 Nov;44(9):2635-8. doi: 10.1016/j.transproceed.2012.09.062.

Abstract

Background: Tacrolimus (Tac) is mainly metabolized by cytochrome P450 3A isoenzymes. In a cohort of heart transplant recipients, we investigated the effect of CYP3A5, CYP3A4, and ABCB1/MDR1 polymorphisms on Tac dose requirements and the risk of developing new-onset diabetes after transplantation (NODAT).

Methods: A total of 65 heart transplant recipients were genotyped for 3 single nucleotide polymorphisms (SNPs) in the CYP3A5 (SNP rs776746), CYP3A4 (SNP rs2740574), and ABCB1 (SNP rs104564). The mean Tac dose values were compared between the genotypes.

Results: CYP3A5 3 homozygotes (nonexpressers; n = 55, 85%) received significantly higher Tac dose compared with CYP3A5 1 carriers (expressers). No different NODAT frequencies were found between the genotypes.

Conclusions: The CYP3A5 polymorphism was the main determinant of Tac dose requirements among heart transplant recipients. This common functional polymorphism had no influence on the risk of developing NODAT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • Adult
  • Analysis of Variance
  • Cytochrome P-450 CYP3A / genetics*
  • Diabetes Mellitus / chemically induced
  • Diabetes Mellitus / genetics
  • Female
  • Genetic Predisposition to Disease
  • Graft Rejection / genetics
  • Graft Rejection / immunology
  • Graft Rejection / prevention & control
  • Graft Survival / drug effects
  • Heart Transplantation / adverse effects
  • Heart Transplantation / immunology*
  • Homozygote
  • Humans
  • Immunosuppressive Agents / administration & dosage*
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / pharmacokinetics
  • Linear Models
  • Logistic Models
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Risk Assessment
  • Risk Factors
  • Tacrolimus / administration & dosage*
  • Tacrolimus / adverse effects
  • Tacrolimus / pharmacokinetics
  • Treatment Outcome
  • Young Adult

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Immunosuppressive Agents
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Tacrolimus