Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients

Transplantation. 2004 Oct 27;78(8):1182-7. doi: 10.1097/


Background: A body-weight-based dose of tacrolimus often results in marked individual diversity of blood drug concentration. Tacrolimus is a substrate for cytochrome P450 (CYP) 3A5 and p-glycoprotein encoded by CYP3A5 and MDR1 (ABCB1), respectively, having multiple single nucleotide polymorphisms. In this study, we genotyped CYP3A5 A6986G, MDR1 G2677(A/T), and C3435T polymorphisms and investigated the association between these polymorphisms and the pharmacokinetics of tacrolimus in renal transplant recipients.

Methods: Thirty consecutive recipients were enrolled in this study. The pharmacokinetics of tacrolimus was analyzed on day 28 after transplant, when the daily dose was adjusted to the target trough level of 10-15 ng/mL. The polymerase chain reaction-restriction fragment length polymorphism and direct sequence method were used for genotyping the CYP3A5 and MDR1 polymorphisms, respectively.

Results: The single tacrolimus dose per body weight was significantly higher in CYP3A5 *1 carriers than CYP3A5 *3/*3 carriers (0.143+/-0.050 vs. 0.078+/-0.031 mg/kg, P<0.001). The dose-adjusted trough level and the area under the concentration-time curve (AUC0-12) were significantly lower in CYP3A5 *1 carriers than CYP3A5 *3/*3 carriers (0.040+/-0.014 vs. 0.057+/-0.024 ng/mL/mg/kg, P=0.015 and 0.583+/-0.162 vs. 0.899+/-0.319, P=0.004), respectively. The MDR1 polymorphism was not associated with any pharmacokinetic parameters.

Conclusions: Kidney transplant recipients with the CYP3A5 *1 allele required a higher daily tacrolimus dose compared with those with the CYP3A5 *3/*3 genotype to maintain both the target trough level and AUC0-12, suggesting that this polymorphism is useful for determining the appropriate dose of tacrolimus.

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Area Under Curve
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics*
  • Dose-Response Relationship, Drug
  • Female
  • Genes, MDR*
  • Heterozygote
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / pharmacokinetics*
  • Kidney Transplantation*
  • Male
  • Middle Aged
  • Osmolar Concentration
  • Polymorphism, Genetic*
  • Polymorphism, Restriction Fragment Length
  • Postoperative Period
  • Tacrolimus / administration & dosage
  • Tacrolimus / pharmacokinetics*


  • Immunosuppressive Agents
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • Tacrolimus