Cytochrome P450 3A5 (CYP3A5) and tacrolimus

CYP3A5 genotyping plays a critical role in personalizing tacrolimus therapy for non-liver transplant patients. Tacrolimus is metabolized primarily by CYP3A5 and has a narrow therapeutic index, making precise dosing essential to reduce the risk of rejection or toxicity.

Genetic variation in CYP3A5 significantly impacts how quickly a patient metabolizes tacrolimus. For example, individuals with at least one functional *1 allele (common in those of African ancestry) require higher initial doses to reach therapeutic levels. Conversely, those with two nonfunctional alleles—such as those with the *3/*3 genotype, which is more prevalent in individuals of European descent—do not require a dose adjustment based on their CYP3A5 genotype, but do metabolize the drug more slowly than those who carry a *1.

Key testing

• 3A5Q | Cytochrome P450 3A5 Genotype, Varies
  • Aids in optimizing treatment with tacrolimus and other drugs metabolized by cytochrome P450 3A5 in patients who are being treated for a non-liver transplant.
  • Identifies individuals with CYP3A5 genetic variants (*3, *6, *7, *8, *9) that affect enzyme function and drug metabolism. If these alleles are not detected, *1 is assigned.
  • Guides initial tacrolimus dose selection based on metabolizer status (normal, intermediate, or poor).
• PGXQP | Focused Pharmacogenomics Panel, Varies
  • This panel identifies individuals with CYP3A5 genetic variants as well as variants inCYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, SLCO1B1, VKORC1, CYP4F2, and rs12777823 to assist with individualized therapy across multiple medications.
  • Recommended for transplant patients on polypharmacy with medications known to have clinically significant drug-gene interactions.

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Therapeutic drug monitoring

While CYP3A5 genotyping offers important guidance for initial tacrolimus dosing, it does not capture the full complexity of drug metabolism, which is influenced by factors such as liver function, drug interactions, and patient adherence. It is also not likely to be predictive of metabolism in patients with a liver transplant, due to the test reflecting the patient’s original liver they were born with but not the new donor liver.

Immunosuppressants like tacrolimus, cyclosporine, and sirolimus all have narrow therapeutic windows and significant variability in absorption and response, making therapeutic drug monitoring (TDM) essential for ongoing dose adjustment.

By combining pharmacogenomic insights with real-time TDM, clinicians can optimize immunosuppression more safely and effectively, reducing the risks of rejection, toxicity, and long-term complications while improving graft survival.¹

Key testing

• TAKRO | Tacrolimus, Blood
  • Useful for monitoring tacrolimus concentration during therapy, particularly in individuals who are taking concomitant cytochrome P450 (CYP) 3A5 inhibitors or inducers.
  • Whole blood analysis captures 90% of tacrolimus bound to erythrocytes, providing a reliable assessment of true drug exposure in patients who have not had a liver transplant.
  • Enables dose optimization to maintain therapeutic levels between 5.0 and 15.0 ng/mL, reducing the risk of rejection while minimizing toxicity.
  • Uses liquid chromatography with tandem mass spectrometry (LC-MS/MS) to deliver precise tacrolimus measurements without cross-reactivity from cyclosporine, sirolimus, or their metabolites — unlike immunoassays, which may overestimate drug levels by up to 30%.

Additional testing

• TACPK | Tacrolimus, Peak, Blood
  • Useful for the assessment of post-dosing (peak) blood tacrolimus concentrations.
• CYSPR | Cyclosporine, Blood
  • Useful for monitoring whole blood cyclosporine concentration during therapy, particularly in individuals who are taking concomitant cytochrome P450 (CYP) 3A4 substrates, inhibitors, or inducers.
• CYCPK | Cyclosporine, Peak, Blood
  • Useful for monitoring whole blood peak cyclosporine concentration during therapy, particularly in individuals coadministered cytochrome P450 (CYP) 3A4 substrates, inhibitors, or inducers.
• EVROL | Everolimus, Blood
  • Useful for managing everolimus immunosuppression in solid organ transplant.
• MPA | Mycophenolic Acid, Serum
  • Useful for monitoring therapy to ensure adequate blood levels and avoid over-immunosuppression.
• SIIRO | Sirolimus, Whole Blood
  • Useful for monitoring whole blood sirolimus concentration during therapy, particularly in individuals coadministered cytochrome P450 (CYP) 3A4 substrates, inhibitors, or inducers.

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References

1. Lemke A, Wright J, May H. Pharmacogenomics and beyond! Customized pharmacotherapy for solid organ transplant recipients. Pharmacotherapy. 2023;43(7):596-608. doi:10.1002/phar.2798
2. Clinical Pharmacogenetics Implementation Consortium (CPIC). Guideline for Tacrolimus and CYP3A5. Published Aug. 18, 2015. Updated Oct. 16, 2023. Accessed Feb. 17, 2025. https://cpicpgx.org/guidelines/guideline-for-tacrolimus-and-cyp3a5/