Tacrolimus and CYP3A5

Tacrolimus (Prograf ® and other brands) is used to prevent the body’s rejection of transplanted organs. In heart, kidney, and liver transplant patients, this drug has proved to be especially helpful. Taking tacrolimus with food, especially when eating meals that are high in fat, lessens the drug’s effect.

Tacrolimus is classified as an immunosuppressant, which means it lowers the ability of human cells to target foreign particles. These foreign particles can include bacteria, viruses, and tissue from another person’s body, such as an organ. It does this by stopping gene expression in human cells by preventing the action of calcineurium phosphatase. This is a compound that normally “turns on” genes that code for cellular immunity. Certain body functions that tacrolimus affects include white blood cell (WBC) function. WBCs normally protect the human body from foreign invaders by producing antibodies, which are chemicals that aid in the killing of the invaders. This suppression of the immune system is beneficial in the setting of organ transplantation, as it allows the new organ to survive attacks from the host’s natural immune response.

Organ transplants have been more successful in recent years due to the use of tacrolimus. The first organ transplants were not as effective because medications were not co-administered with surgeries. Transplant patients produce antibodies in response to the newly transplanted organ because the new organ is interpreted as a threat to the body. The activation of the host’s immune system damages the transplanted organ and eventually leads to rejection. Tacrolimus allows the transition of living with new organs to occur more pleasantly, as it prevents these attacks on transplanted organs and allows the body to become accustomed to having foreign tissue in the body.

The gene that mostly affects tacrolimus is called cytochrome P450-3A5 (CYP3A5- pronounced sip-three-ay-five). CYP3A5 codes for a metabolizing enzyme, a protein that breaks down chemical compounds for the body’s use. The common CYP3A5 allelic variants can be broken down into two broad categories: functional and nonfunctional. Functional alleles are CYP3A5*1 whereas nonfunctional alleles include CYP3A5-*3,*6, and *7.

To be effective, tacrolimus needs to be present in a certain concentration in the body. If the active form of the drug is metabolized rapidly, this decreases the chance of tacrolimus reaching the appropriate concentration. In contrast, if tacrolimus is metabolized slowly, the chance of reaching target concentration increases. Individuals with two copies of functional alleles, *1/*1, are categorized as extensive metabolizers. These individuals metabolize the active drug to a non-active form quicker and may require an increase in starting dosage to compensate for this. Individuals with one functional and one nonfunctional allele (*1/*3,*6, or *7) are intermediate metabolizers, and it is found that they too tend to require an increase in starting dose. An individual with two nonfunctional alleles (two copies of *3, *6, or *7) is a poor metabolizer which means they break down the active drug slower compared to other phenotypes. This leads to an increase in active drug concentration in the body; no dosage adjustment is typically needed as the individual is more likely to reach target concentration.

Elizabeth is a 50-year-old Caucasian female who recently had a kidney transplant. Her doctor is in the process of prescribing her an antirejection medication, tacrolimus. When speaking with the doctor about the tacrolimus it was mentioned that the dose Elizabeth would need could vary due to a mutation in her CYP3A5 genotype. This was mentioned due to the fact that the mutation is more common in Caucasian females. Her doctor offered genetic testing to see if she did have the mutation, however, she refused the testing and let the doctor prescribe her the normal recommended dose of tacrolimus. Two weeks later, Elizabeth is checked into the hospital for peripheral edema and a sudden onset of hypertension. Her doctors perform a genetic test and confirm that she does have the CYP3A5 mutation and should be receiving a lower dose of her tacrolimus.

One month later, the same doctor begins treating a 40-year-old Caucasian female, Marie, who recently had a liver transplant. The doctor begins to explain the risks of the mutation in the CYP3A5 genotype to Marie after his previous experience with Elizabeth. Marie agrees to genetic testing for the CYP3A5 genotype and learns that she does in fact have the mutation. This allows her doctor to prescribe the proper dose for Marie and she is able to make a full recovery without any adverse events.

Gene sequencing does not completely rule out the risks of acute toxicities related to anti-rejection medications, nor does it guarantee the medications will work. However, genetic testing is a guide to personalize the treatment of patients maximizing benefit and minimizing harm.

The links below provide access to important articles and information relative to tacrolimus. The links are to external websites and will be checked regularly for consistency.

• Tacrolimus Prescribing Information
• Tacrolimus Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: Tacrolimus

Birdwell KA, Decker B, Barbarino JM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clin Pharmacol Ther. 2015 Jul;98(1):19-24.

Dai Y, Hebert MF, Isoherranen N, et al. Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro. Drug Metab Dispos. 2006 May;34(5):836-47.

Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer Clinical Drug Information Inc. c.1978-2015. Tacrolimus (systemic); [cited 2015 Oct 24]; [about 22 screens]. Available from: http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/1801799.

Tacrolimus [package insert on the Internet]. Bethesda (MD): U.S. National Library of Medicine; [updated 2016 Mar 18; cited 2017 May 23]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bd447ffa-9196-4c3c-accf-5adf29b84665.

Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit. 1995 Dec;17(6):584-91.

Zuo XC, Ng CM, Barrett JS, et al. Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis. Pharmacogenet Genomics. 2013 May;23(5):251-61.