What is the metabolism of tacrolimus (immunosuppressive medication) in patients with normal liver function who have undergone organ transplantation?

Metabolism of Tacrolimus

Tacrolimus undergoes extensive hepatic metabolism primarily via the cytochrome P450 3A4 and 3A5 enzyme systems (CYP3A4 and CYP3A5), with CYP3A5 being the predominant enzyme responsible for its clearance in patients who express functional CYP3A5 protein. 1, 2

Primary Metabolic Pathways

Tacrolimus is metabolized through two critical pathways:

• Hepatic CYP3A enzymes: CYP3A4 and CYP3A5 are the major cytochrome P450 subtypes catalyzing phase I metabolism of tacrolimus in the liver 1, 2
• Intestinal metabolism: First-pass metabolism occurs in the gut via CYP3A4 enzymes and P-glycoprotein (P-gp/ABCB1) efflux pump, which limits oral absorption 1, 3

The drug is highly lipophilic and requires extensive metabolism before excretion from the body 2

Major Metabolites

Eight tacrolimus metabolites have been identified, with two being clinically significant:

• 13-O-demethyl tacrolimus (M-I): One of the two major metabolites 4
• 15-O-demethyl tacrolimus (M-III): The second major metabolite, which may have nephrotoxic and myelotoxic effects and correlates negatively with estimated glomerular filtration rate (eGFR) and red blood cell counts 4

Higher M-III concentrations are associated with increased infection incidence in kidney transplant recipients 4

Genetic Polymorphisms Affecting Metabolism

CYP3A5 polymorphism is the single most important genetic determinant of tacrolimus pharmacokinetics:

• CYP3A5*3 allele (6986A>G): This frequent polymorphism causes a splicing defect resulting in absent functional CYP3A5 protein in homozygous carriers (CYP3A5*3/*3, "non-expressers") 1
• *CYP3A53/3 patients* have higher dose-adjusted tacrolimus blood concentrations and require lower tacrolimus doses compared to CYP3A5*1 carriers 1, 5
• *CYP3A51/1 carriers* (expressers) require significantly higher tacrolimus doses to achieve target concentrations, particularly in liver transplant recipients where the donor liver genotype determines metabolism 5

CYP3A4 variants have less consistent effects:

• CYP3A4*1B (-392A>G): Rare variant with unclear clinical significance; some studies show lower dose-adjusted trough levels in carriers 1
• CYP3A4*22: A loss-of-function variant reducing CYP3A4 protein production 6
• *Combined CYP3A53/3 and CYP3A422/22 genotype:* Extremely rare in Caucasians but results in profoundly reduced tacrolimus metabolism, with patients requiring only ~2.5 mg/day on average (342% increase in dose-normalized trough compared to wild-type) 6

Drug Interactions Affecting Metabolism

Because tacrolimus is metabolized via CYP3A4, numerous medications alter its blood levels through enzyme inhibition or induction:

CYP3A4 inhibitors that INCREASE tacrolimus levels include: 1

• Azole antifungals (ketoconazole, itraconazole, fluconazole)
• Macrolide antibiotics (erythromycin, clarithromycin)
• Calcium channel blockers (diltiazem, verapamil, nifedipine)
• Protease inhibitors
• Cyclosporine A

CYP3A4 inducers that DECREASE tacrolimus levels include: 1

• Anti-convulsants: carbamazepine, phenobarbital, phenytoin
• Antibiotics: rifampin, rifabutin
• St. John's Wort
• Orlistat

P-glycoprotein interactions also affect tacrolimus:

• Carvedilol increases tacrolimus levels by inhibiting P-glycoprotein despite not affecting CYP3A4 1

Clinical Implications for Monitoring

Due to the narrow therapeutic window (5-15 ng/mL) and extensive metabolic variability, therapeutic drug monitoring is mandatory: 1, 7

• Monitor tacrolimus trough levels daily until stable therapeutic range is achieved 1
• Check levels every 2-3 days until hospital discharge, then gradually increase intervals to every 1-2 weeks in the first 1-2 months post-transplant 1
• Once stable, monitor every 1-2 months 1
• When any CYP3A4 inhibitor or inducer is added or removed, check tacrolimus levels within 1-3 days and continue monitoring every 2-3 days until stable 7, 8

Critical Pitfalls to Avoid

Common errors in managing tacrolimus metabolism include:

• Failing to check for drug interactions before prescribing new medications to transplant recipients 1, 8
• Not accounting for hepatic dysfunction, which substantially reduces tacrolimus clearance in patients with severe hepatic impairment (Child-Pugh score >10) 9
• Ignoring the effect of gastrointestinal transit time changes—chronic diarrhea can paradoxically increase tacrolimus absorption by reducing intestinal CYP3A4 and P-gp exposure time 3
• Inadequate monitoring frequency when metabolic conditions change 8
• Not considering donor liver CYP3A5 genotype in living-donor liver transplantation, where the graft genotype determines tacrolimus metabolism 5

High-fat meals decrease tacrolimus oral absorption area under the curve by 37% with a 77% decrease in maximum plasma concentration 1