Tacrolimus: the drug where making the enzyme means needing more, not less
Every other page on this site follows the same intuition: slow metabolism means the drug piles up. Tacrolimus and CYP3A5 run the opposite way, and getting the direction wrong is exactly the mistake the gene test exists to prevent.
Also sold as: Prograf, Advagraf, Envarsus.
What tacrolimus is
Tacrolimus is an immunosuppressant given after an organ transplant to stop the body rejecting the new organ. It is taken daily, indefinitely, and it has a narrow therapeutic window: too little and rejection risk climbs, too much and it damages the kidneys and raises infection risk. Because that window is so tight, transplant teams measure its blood level constantly, especially in the first weeks.
Why your genes come into it
CYP3A5 is one of the enzymes that break tacrolimus down, and here the naming is the trap. Someone who carries a working copy of the gene, an expresser, breaks the drug down faster, so a standard dose leaves them with a lower blood level than intended and they need more drug to reach the target. Someone who does not make the enzyme, which is the common state in people of European ancestry, clears the drug more slowly and a standard starting dose is about right. That is why the guidance raises the starting dose for expressers rather than lowering it, the reverse of what the word metabolizer usually implies elsewhere. Blood-level monitoring then does the fine tuning from the first days regardless of genotype.
What published guidance says
The rows below restate CPIC's published guidance for each possible CYP3A5 result, and they describe a starting point a transplant team weighs before its own monitoring takes over, not a dose for anyone to set. Tacrolimus dosing after a transplant is driven by blood levels measured repeatedly from the outset, and any genotype-informed starting dose comes from the transplant service's own testing, not from a re-analysis of a consumer file.
CYP3A5
| If your CYP3A5 result is | What that means | Published CPIC guidance |
|---|---|---|
| Intermediate Metabolizer | Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrations. | Per CPIC (A): "Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3 mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments." |
| Normal Metabolizer | Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrations. | Per CPIC (A): "Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3 mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments." |
| Poor Metabolizer | Higher ("normal") dose-adjusted trough concentrations of tacrolimus and increased chance of achieving target tacrolimus concentrations. | Per CPIC (A): "Initiate therapy with standard recommended dose. Use therapeutic drug monitoring to guide dose adjustments." |
| Possible Intermediate Metabolizer | Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrations. | Per CPIC (A): "Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3 mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments." |
Can your DNA file answer this?
CYP3A5 is not part of the standard chip or variant-file report. It is a Deep Read gene, read from aligned reads in a BAM or CRAM file, and where the reads do not resolve the diplotype the result is Indeterminate. This is also a page to read for understanding rather than action. A transplant is managed with frequent tacrolimus blood-level tests from day one, so the clinical dose is set by direct measurement and by the service's own genotyping if it uses it. A consumer re-analysis here is background that explains why doses differ between people, not an input to a live transplant.
A genotyping chip reads only a few hundred thousand pre-selected positions, about 0.02% of your genome, chosen for common variation. It does not sequence the rest, so it cannot find the rare or novel pathogenic variants the clinical and carrier modules look for: a “no finding” from chip data means “this chip never looked”, far more so than with whole-genome sequencing. Chip data suits common-variant traits, pharmacogenomic tag SNPs, and haplogroup ancestry, not clinical or carrier screening.
Common questions
I am a CYP3A5 expresser. Does that mean tacrolimus is dangerous for me?
No. It means that at a standard starting dose you would tend to run a lower blood level than intended, because you clear the drug faster, so the guidance starts expressers higher. It is a reason a transplant team adjusts the opening dose, not a safety alarm, and the constant blood-level monitoring that follows corrects for it either way.
Why is this the opposite of the other drug pages here?
Because the phenotype label describes enzyme activity, and for tacrolimus more activity means faster removal of the drug, so more is needed rather than less. On most other pages the drug is either activated by the enzyme or cleared in a way where slow metabolism causes build-up. Tacrolimus is the clean example of why you cannot assume the direction and have to read the actual guidance.
Should I show my transplant team a consumer CYP3A5 result?
You can mention it, but it will not replace their own testing, and it should never drive a dose change on its own. Transplant services that use CYP3A5 genotyping order it themselves, validated for clinical use, and pair it with the blood-level monitoring that governs the dose from the start. A consumer re-analysis is context for a conversation, not a clinical result.
Can my 23andMe file answer this?
No. CYP3A5 is read from aligned reads rather than from array positions, so it is part of the Deep Read panel rather than a chip result, and an unresolved diplotype is reported as Indeterminate rather than guessed.