Is Prograf affected by genetics?

Yes — the active ingredient is metabolized by a gene known to vary between individuals.

Relevant genes: CYP3A5

Used for: Preventing organ rejection after kidney, liver, and heart transplant

Prograf (tacrolimus) is the backbone of most modern solid organ transplant regimens, and its pharmacogenetics involves an unusual twist. CYP3A5, the enzyme most responsible for tacrolimus metabolism, is non-functional in most people of European descent because of a common loss-of-function variant (CYP3A5*3). It remains functional in the majority of people of African descent. That reverses what pharmacogenetics usually looks like: the European phenotype is effectively the poor metabolizer, while CYP3A5 expressers (more common in African and some other populations) clear tacrolimus 1.5 to 2 times faster and need correspondingly higher doses. Getting the right dose in the first weeks after transplant is critical for graft survival, and many transplant centers now genotype CYP3A5 before starting tacrolimus.

What's in Prograf

tacrolimus affected by CYP3A5

Affected by CYP3A5 · CPIC, FDA · Strong evidence

Tacrolimus has a narrow therapeutic window: too little and the transplant rejects, too much and kidney toxicity and infection risk rise. It's metabolized primarily by CYP3A5 (in expressers) and CYP3A4. The critical variant is CYP3A5*3, which produces no functional enzyme. About 80 to 85 percent of people of European descent are *3/*3 homozygotes and are non-expressers. In contrast, roughly 60 to 80 percent of people of African descent carry at least one functional CYP3A5 allele. Dose requirements differ substantially: non-expressers typically need around 0.1 mg/kg/day; expressers may need 0.15 to 0.2 mg/kg/day to achieve the same trough level.

Read the full tacrolimus genetics guide →

Tacrolimus phenotype recommendations

Published guidance from CPIC and FDA on how tacrolimus should be dosed or substituted based on your CYP3A5 phenotype.

Phenotype	What it means	Recommendation	Evidence
Normal Metabolizer CYP3A5	Your body breaks down tacrolimus faster than most people, which means a standard dose may not reach effective levels. A higher starting dose is recommended to help prevent organ rejection.	CPIC Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments FDA Consider a higher starting dose. Measure trough whole blood tacrolimus concentrations and adjust dosage to achieve target levels.	Strong
Intermediate Metabolizer CYP3A5	Your body breaks down tacrolimus somewhat faster than most people, which means a standard dose may not reach effective levels. A higher starting dose is recommended to help prevent organ rejection.	CPIC Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments FDA Adjust dosage based on genotype and therapeutic drug monitoring. Refer to FDA labeling for specific dosing recommendations.	Strong
Poor Metabolizer CYP3A5	Your body processes tacrolimus at a slower rate, which means the standard dose should achieve effective drug levels. The usual starting dose is appropriate for you.	CPIC Initiate therapy with standard recommended dose. Use therapeutic drug monitoring to guide dose adjustments FDA Initiate therapy with recommended starting dose.	Strong
Indeterminate CYP3A5	The impact of your genotype on response to this drug is unknown	CPIC + FDA Initiate therapy with recommended starting dose.	—
Not available CYP3A5	The impact of your genotype on response to this drug is unknown	CPIC + FDA Initiate therapy with recommended starting dose.	—

Sources: CPIC, FDA

The gene behind the guidance

CYP3A5 Cytochrome P450 3A5

CYP3A5 is unusual: most people of European descent carry a non-functional variant and don't produce active enzyme at all. Most people of African descent do. For drugs like tacrolimus (used after organ transplant), this reverses the usual pharmacogenetic picture: the "normal" European phenotype is actually the poor metabolizer, while most African-descended patients are expressers who clear tacrolimus much faster and need higher doses.

Transplant centers increasingly genotype CYP3A5 before starting tacrolimus, because getting the dose right in the first weeks is critical to graft survival.

See all drugs affected by CYP3A5 →

Browse the full drug-class: Immunosuppressants.

What this means for you

If you or a loved one is preparing for a kidney, liver, or heart transplant, ask the transplant team whether CYP3A5 genotyping will be part of the pre-operative workup. Many major US transplant centers now do this automatically. The benefit is getting to therapeutic trough levels faster in the first week post-transplant, which is the window where under-dosing (rejection) and over-dosing (toxicity) both carry the highest stakes. This isn't a test you can shop for separately once you're on tacrolimus, because your maintenance dose has usually already found steady state by then, but it's high-value at the start.

FAQ

Why do CYP3A5 expressers need more tacrolimus, not less?

CYP3A5 is a clearance enzyme. The more of it you have, the faster you clear tacrolimus out of your blood. To achieve the same trough level (the target for graft protection), you need to put more drug in at the start. This is the opposite of the usual pharmacogenetic story, which is why it trips up both patients and clinicians who are used to thinking of pharmacogenetic variants as dose-reducers.

Does race-based dosing matter if we have the genetic test?

The genetic test should take precedence. Race is only a proxy for CYP3A5 status, and a plurality of African-American patients are non-expressers despite the population base rate. Using race alone to set tacrolimus doses is imprecise and risks under- or over-dosing individuals. Where a CYP3A5 genotype is available, it should be used directly.

Are there other transplant drugs where pharmacogenetics matters?

Mycophenolate and everolimus, both commonly used alongside tacrolimus, have some pharmacogenetic signal but less clinical impact. Cyclosporine, which is used instead of tacrolimus in some regimens, is metabolized primarily by CYP3A4 rather than CYP3A5 and doesn't have the same CYP3A5 genotype dependence. CYP3A5 is most distinctive for tacrolimus.

Find out how your genetics affect Prograf

This page describes the general pharmacogenetics. A Gene2Rx report analyzes your own DNA to tell you which metabolizer group you fall into, across every medication.

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Informational only — not medical advice. Pharmacogenetic guidance describes population-level patterns; your individual response depends on many factors. Never start, stop, or change a medication without talking to your prescribing clinician.