Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome p4503A5 and P-glycoprotein correlate with dose requirement

Transplantation. 2002 Dec 15;74(11):1486-9. doi: 10.1097/00007890-200212150-00002.


Background: There is marked heterogeneity in blood concentrations of tacrolimus following standard body-weight-based dosing. This is most apparent in black patients, who have a higher dose requirement when compared with other ethnic groups. Differences in intestinal P-glycoprotein and hepatic and intestinal cytochrome P4503A activity have been postulated as contributing to this problem.

Methods: The dose-normalized blood concentrations of tacrolimus at 3 months after renal transplantation were related to CYP3AP1 and multiple drug resistance (MDR)-1 genotypes determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis.

Results: We found that a single nucleotide polymorphism in the CYP3AP1 pseudogene (A/G(44)) that previously has been noted to be more common in African Americans and strongly associated with hepatic CYP3A5 activity correlated well with the tacrolimus dose requirement. A weaker association was found for a polymorphism in the MDR-1 gene, which influences intestinal P-glycoprotein expression.

Conclusions: The CYP3AP1 genotype is a major factor in determining the dose requirement for tacrolimus, and genotyping may be of value in planning patient-specific drug dosing.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Adolescent
  • Adult
  • Aged
  • Asian People / genetics
  • Black People / genetics
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dose-Response Relationship, Drug
  • Female
  • Genes, MDR / physiology
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Pharmacogenetics*
  • Polymorphism, Single Nucleotide / physiology*
  • Pseudogenes / genetics
  • Tacrolimus / administration & dosage*
  • Tacrolimus / therapeutic use
  • White People / genetics


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • Tacrolimus