From the Guidelines
Tacrolimus is primarily metabolized through the liver, specifically via the cytochrome P450 3A4 (CYP3A4) enzyme system. This immunosuppressive medication undergoes extensive hepatic metabolism, which is crucial for understanding its pharmacokinetics and potential drug interactions 1. The liver's role in tacrolimus metabolism is vital, as medications that inhibit or induce CYP3A4 can significantly affect tacrolimus blood levels, potentially leading to toxicity or therapeutic failure. Additionally, patients with liver dysfunction may require dose adjustments due to impaired metabolism of the drug. While the liver is the primary site of metabolism, tacrolimus and its metabolites are primarily excreted through the biliary system, with only a small amount eliminated through the kidneys.
Some key points to consider when prescribing tacrolimus include:
- Medications that interact with the CYP3A4 enzyme system can affect tacrolimus levels, such as imidazoles, which can increase tacrolimus trough levels 1
- High-fat meals can decrease the oral absorption of tacrolimus, and St John's wort may decrease tacrolimus levels 1
- The use of tacrolimus in combination with other immunosuppressive drugs, such as MMF or AZA, can help preserve renal function and allow for lower tacrolimus trough levels 1
- Tacrolimus trough levels should be kept at 6-10 ng/ml during the first month, followed by 4-8 ng/ml thereafter, to minimize the risk of toxicity and therapeutic failure 1
Overall, the hepatic metabolism of tacrolimus highlights the importance of therapeutic drug monitoring and careful consideration of potential drug interactions when prescribing this medication.
From the FDA Drug Label
Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A4 and CYP3A5). The liver is the primary organ where tacrolimus is metabolized, as it is extensively metabolized by the cytochrome P-450 system, which is mainly located in the liver 2.
From the Research
Organ Metabolism of Tacrolimus
- Tacrolimus is metabolized predominantly in the liver and intestine by cytochrome P450 3A (CYP3A) 3, 4, 5, 6, 7
- The liver plays a significant role in the metabolism of tacrolimus, with CYP3A4 and CYP3A5 being the primary enzymes involved 3, 5, 7
- The intestine also contributes to the metabolism of tacrolimus, with CYP3A4 and CYP3A5 present in the intestinal tissue 6
- The metabolism of tacrolimus in the liver and intestine can be affected by various factors, including genetic polymorphisms, drug interactions, and food intake 5, 6, 7
Enzymes Involved in Tacrolimus Metabolism
- CYP3A4 and CYP3A5 are the primary enzymes involved in the metabolism of tacrolimus 3, 4, 5, 6, 7
- CYP3A5 is a polymorphically expressed enzyme, and its presence can affect the metabolism of tacrolimus 3, 5, 7
- The activity of CYP3A4 and CYP3A5 can be influenced by various factors, including drug interactions and genetic polymorphisms 4, 5, 6, 7
Factors Affecting Tacrolimus Metabolism
- Genetic polymorphisms, such as CYP3A5 polymorphism, can affect the metabolism of tacrolimus 3, 5, 7
- Drug interactions, including interactions with CYP3A inhibitors and inducers, can affect the metabolism of tacrolimus 4, 5, 6, 7
- Food intake can also affect the metabolism of tacrolimus, with certain foods influencing the activity of CYP3A4 and CYP3A5 7