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Clinical context

Tacrolimus is a commonly used immunosuppressant drug prescribed after solid organ and hematopoietic stem cell transplantation. It has a narrow therapeutic window and large inter-patient pharmacokinetic variability.

Tacrolimus and pharmacogenomics

  • Tacrolimus is a macrolide immunosuppressant that binds to the FK binding protein 12 (FKBP12) in T lymphocytes. This complex binds with calcineurin, which leads to the inhibition of both interleukin-2 production and T lymphocyte activation.
  • It is one of the most frequently prescribed immunosuppressant medicines in both adult and paediatric recipients of solid organ and hematopoietic stem cell transplantation.
  • Its use is complicated by high inter-patient pharmacokinetic variability and a narrow therapeutic window. Therapeutic drug monitoring is routinely recommended.
  • Tacrolimus metabolism occurs by hepatic and intestinal cytochrome P450 3A (CYP3A) enzyme isoforms (CYP3A5 and, to a lesser extent, CYP3A4).
  • Blood concentrations of tacrolimus are influenced by CYP3A5 enzyme expression and function, with substantial evidence linking CYP3A5 genotype to variability in trough concentrations.
  • Unlike CYP3A4 and other drug-metabolising CYP enzymes, absence of functional CYP3A5 is the norm in many populations. This is particularly notable in people of European ancestry, where 80%–85% of the population are homozygous for the non-functional CYP3A5*3 allele, making them CYP3A5 poor metabolisers.
  • Evidence suggests that expressers of CYP3A5 (those with at least one functional CYP3A5 allele) have significantly lower dose-adjusted trough concentrations of tacrolimus, compared to non-expressers (those with two non-functional CYP3A5 alleles, also known as poor metabolisers). These individuals require 1.5 to two times the dose to achieve similar tacrolimus blood concentration.
  • The current evidence for the usefulness of CYP3A5 genotyping to guide tacrolimus dosing is largely restricted to the effect of CYP3A5 genetic variants on pharmacokinetic parameters (tacrolimus blood concentrations). Most of this evidence is from research studies on kidney transplant patients who have been prescribed tacrolimus.
  • Current evidence linking genetic variation in CYP3A5 to hard clinical outcomes in patients on tacrolimus is limited and inconsistent.
  • Knowledge of a patient’s CYP3A5 genotype may be most useful when first starting tacrolimus to aid quicker attainment of therapeutic blood concentrations (in CYP3A5 expressers) before and alongside therapeutic drug monitoring.

Genomic testing for CYP3A5 variants


For clinicians


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  • Last reviewed: 04/08/2023
  • Next review due: 04/08/2025
  • Authors: Lucy Galloway, Dr John McDermott
  • Reviewers: Dr Charlotte Barker, Dr Emma Magavern