Metabolism of Tacrolimus (FK506) and Recent Topics in Clinical Pharmacokinetics

doi:10.2133/dmpk.22.328

Drug Metabolism and Pharmacokinetics

Volume 22, Issue 5, 2007, Pages 328-335

https://doi.org/10.2133/dmpk.22.328 Get rights and content

Summary:

Tacrolimus (FK506), an immunosuppressive drug, is co-medicated with multiple drugs under clinical conditions. Tacrolimus is highly lipophilic and is excreted from the body after receiving extensive metabolism. Due to its narrow therapeutic window following organ transplantation, tacrolimus requires therapeutic drug monitoring by an enzyme immunoassay using the monoclonal antibody raised against tacrolimus. Therefore, metabolism studies including drug-drug interaction and metabolite identification studies are essential for the efficient development and clinically optimal usage of this drug. Tacrolimus was metabolized by the cytochrome P450 (CYP) 3A subfamily. Metabolic drug-drug interaction studies were conducted to provide information regarding the optimal usage of tacrolimus, and its metabolism was inhibited by known CYP3A inhibitors such as ketoconazole, cyclosporine A, and nifedipine. Recent reports on clinical pharmacokinetics indicate that dose levels of tacrolimus need to be adjusted in transplant patients with CYP3A5 polymorphism.

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Cited by (205)

Safety analysis of co-administering tacrolimus and omeprazole in renal transplant recipients – A review
2023, Biomedicine and Pharmacotherapy
Tacrolimus is a calcineurin inhibitor used to prevent rejection in allogenic solid organ transplant recipients, which is metabolized in the liver with cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5). In turn, proton pump inhibitors (PPIs), such as Omeprazole - a substrate and inhibitor of CYP2C19 and CYP3A4 enzymes - are administered to kidney transplant patients in order to prevent duodenal and gastric ulcer disease, associated with the glucocorticoid treatment. Simultaneous administration of both drugs in renal patients has the potential to trigger drug interactions. In fact, there are several mechanisms which may impact the pharmacokinetics of tacrolimus. Inhibition of the CYP2C19 isoform may suppress the metabolism of omeprazole, subsequently altering its metabolic pathway to be metabolized by the CYP3A4 enzyme in order to maintain adequate biotransformation. Therefore, the competition for CYP3A4 may affect the metabolism of tacrolimus and result in its increased plasma concentrations, as well as in adverse reactions. Another mechanism has been related to the genetic polymorphism of the CYP2C19 isoform. Since all these interactions may lead to dysfunctions of the transplanted kidney, it seems significant to eliminate their consequences, for instance via the administration of drugs which are neither substrates, nor inhibitors of the CYP3A4 enzyme. Finally, the nephrotoxic effect of omeprazole should also be accounted for. Bearing in mind the aforementioned observations, the aim of the presented paper was to review the available studies addressing the effect of omeprazole on the pharmacokinetics of tacrolimus.
On the usefulness of four in vitro methodologies in screening for product related differences in tacrolimus exposure after oral administration of amorphous solid dispersions with modified release characteristics in the fasted state
2022, Journal of Drug Delivery Science and Technology
To investigate the usefulness of four in vitro methodologies in screening for product related differences in tacrolimus exposure after oral administration of amorphous solid dispersions with modified release characteristics in the fasted state.
Initially, Advagraf® (5 mg tacrolimus/capsule), Envarsus® (4 mg tacrolimus/tablet) and a modified release Test Tablet (5 mg tacrolimus/tablet) were subjected to in vitro biorelevant performance testing simulating fasted state conditions using a small-scale two-stage biphasic system, a small-scale two-stage dissolution – permeation (D-P) system, the compendial apparatus IV (open loop mode) and the biorelevant gastrointestinal transfer (BioGIT) system. Early and total exposure, after single dose administrations of the three products to twelve healthy adults in the fasted state on a crossover basis, were then evaluated. Subsequently, the usefulness of in vitro data in qualitatively predicting product related differences in early exposure and in total exposure were assessed.
Product related differences in tacrolimus early exposure were successfully predicted by data collected with compendial apparatus IV. The two-stage biphasic system was useful for predicting differences in early exposure between the non-disintegrating Envarsus® and the disintegrating products (Advagraf® or Test Tablet). BioGIT data were useful only for discussing clinical data early after administration of the two disintegrating products. Prediction of product related differences in total exposure was successful only when the compendial apparatus IV was used for comparing the two disintegrating products.
Biorelevant in vitro performance testing with compendial apparatus IV was useful for qualitatively predicting differences in tacrolimus early and total exposure after administration of disintegrating products with modified release characteristics in the fasted state.
Trans-eQTLs of the CYP3A4 and CYP3A5 associated with tacrolimus trough blood concentration in Chinese renal transplant patients
2022, Biomedicine and Pharmacotherapy
This study aimed to systematically investigate trans-eQTLs of CYP3A4 and CYP3A5 affecting tacrolimus trough blood concentrations in Chinese renal transplant patients. We used Plink v1.90 to perform data quality control and linear regression analysis on GTEx v8 data. SNPs with p-value < 0.05 were selected and the GTEx eQTL Calculator was used to further prioritize the eQTLs of CYP3A4 and CYP3A5 in the liver and small intestine. The eQTLs with a p-value < 5 × 10⁻⁵ and MAF ≥ 0.05 in the CHB population were selected as candidate eQTLs. The genotyping of candidate eQTLs was performed using high-resolution melting (HRM) assays and Sanger DNA sequencing. This study included 845 Chinese renal transplant patients who received tacrolimus as an immunosuppressive agent. Association between 103 candidate eQTLs and log-transformed tacrolimus concentration/dose ratio (log (C₀/D)) in this cohort was conducted using the SNPassoc package of R software. In the end, a total of 75,632 liver eQTLs of CYP3A4, 69,558 liver eQTLs of CYP3A5, 48,596 small intestine eQTLs of CYP3A4 and 28,616 small intestine eQTLs of CYP3A5 were obtained using the GTEx v8 eQTL Calculator. Of the 103 candidate eQTLs, rs75727207, rs181294422 and rs28522676 were significantly associated with tacrolimus log(C₀/D) in different genetic models. We discovered a substantial number of novel eQTLs of CYP3A4 and CYP3A5 in liver and small intestine, also found that rs75727207, rs181294422 and rs28522676 may affect tacrolimus trough blood concentrations in Chinese renal transplant patients.
Determination of tacrolimus, three mono-demethylated metabolites and a M1 tautomer in human whole blood by liquid chromatography – tandem mass spectrometry
2021, Journal of Pharmaceutical and Biomedical Analysis
The immunosuppressant tacrolimus is the primary drug used in kidney transplantation to prevent organ rejection.
A sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to measure tacrolimus and its three known mono-demethylated metabolites 13-O-desmethyl tacrolimus (M1), 31-O-desmethyl tacrolimus (M2), 15-O-desmethyl tacrolimus (M3).
By generating the metabolites to use as standards after incubation of tacrolimus with rat liver microsomes, we discovered multiple M1 peaks which we identified as two tautomers of M1. The M1 tautomer II was also successfully validated in this method. The separation and purification of the metabolites and tautomers were performed by semi-preparative liquid chromatography with UV-detection, while confirmation was done by UPLC-MS/MS and Nuclear Magnetic Resonance. For quantification an easy sample preparation was performed with zinc sulfate and acetonitrile as cell lyses and precipitation. Detection was performed in positive electrospray ionization. By better characterization of the metabolites and the tautomers, we could possibly explain insight into the clinical condition and thus adjust the immunosuppressant therapy individually per patient.
Calibration curves were linear for all compounds. Precision was assessed according to the NCCLS EP5-T guideline, being below 15 % and mean recoveries were between 93 and 110 % for tacrolimus, its three metabolites and the M1 tautomer II. The validated method was successfully applied in a cohort of 20 patients after kidney transplantation.
Proteome-wide Mendelian randomization identifies therapeutic targets for ankylosing spondylitis
2024, Frontiers in Immunology
ANALYTICAL METHOD DEVELOPMENT AND VALIDATION OF ASCOMYCIN CONTENT IN TACROLIMUS API BY USING RP HPLC
2024, International Journal of Pharmaceutical Sciences and Research

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Drug Metabolism and Pharmacokinetics

Summary:

References (32)

Metabolism of FK506, a potent immunosuppressive agent, by cytochrome P450 3A enzymes in rat, dog and human liver mcirosomes

Biochem. Pharmacol.

In vitro metabolism of FK-506 in rat, rabbit, and human liver microsomes: Identification of a major metabolite and of cytochrome P450 3A as the major enzymes responsible for its metabolism

Arch. Biochem. Biophys.

Specificity of therapeutic drug monitoring of tacrolimus in kidney transplant patients

Transplant. Proc.

Human P-glycoprotein transports cyclosporin A and FK506

J. Biol. Chem.

An up-date review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients

Pharmacol. Ther.

Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms

Am. J. Transplant.

Iyakuhin Kenkyu

Clinical pharmacokinetics of tacrolimus

Clin. Pharmacokinet.

Mechanism of clinically relevant drug interactions associated with tacrolimus

Clin. Pharmacokinet.

Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation

Clin. Pharmacokinet.

Absorption, distribution, metabolism and excretion of tacrolimus (FK506) in the rat

Xenobio. Metab. Dispos.

Comparison of tacrolimus (FK506) levels determined by three different methods in the rat blood

Xenobio. Metab. Dispos.

Isolation, identification, and biological activities of oxidative metabolites of FK506, a potent immunosuppressive macrolide lactone

Drug Metab. Dispos.

Further metabolism of FK506 (tacrolimus). Identification and biological activities of the metabolites oxidized at multiple sites of FK506

Drug Metab. Dispos.

Oxidative metabolism of tacrolimus and its metabolite by human cytochrome P450 3A subfamily

Xenobio. Metab. Dispos.

Cited by (205)

Safety analysis of co-administering tacrolimus and omeprazole in renal transplant recipients – A review

On the usefulness of four in vitro methodologies in screening for product related differences in tacrolimus exposure after oral administration of amorphous solid dispersions with modified release characteristics in the fasted state

Trans-eQTLs of the CYP3A4 and CYP3A5 associated with tacrolimus trough blood concentration in Chinese renal transplant patients

Determination of tacrolimus, three mono-demethylated metabolites and a M1 tautomer in human whole blood by liquid chromatography – tandem mass spectrometry

Proteome-wide Mendelian randomization identifies therapeutic targets for ankylosing spondylitis

ANALYTICAL METHOD DEVELOPMENT AND VALIDATION OF ASCOMYCIN CONTENT IN TACROLIMUS API BY USING RP HPLC

ReviewMetabolism of Tacrolimus (FK506) and Recent Topics in Clinical Pharmacokinetics

Summary:

Biochem. Pharmacol.

Arch. Biochem. Biophys.

Transplant. Proc.

J. Biol. Chem.

Pharmacol. Ther.

Am. J. Transplant.

Iyakuhin Kenkyu

Clinical pharmacokinetics of tacrolimus

Clin. Pharmacokinet.

Mechanism of clinically relevant drug interactions associated with tacrolimus

Clin. Pharmacokinet.

Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation

Clin. Pharmacokinet.

Absorption, distribution, metabolism and excretion of tacrolimus (FK506) in the rat

Xenobio. Metab. Dispos.

Comparison of tacrolimus (FK506) levels determined by three different methods in the rat blood

Xenobio. Metab. Dispos.

Isolation, identification, and biological activities of oxidative metabolites of FK506, a potent immunosuppressive macrolide lactone

Drug Metab. Dispos.

Further metabolism of FK506 (tacrolimus). Identification and biological activities of the metabolites oxidized at multiple sites of FK506

Drug Metab. Dispos.

Oxidative metabolism of tacrolimus and its metabolite by human cytochrome P450 3A subfamily

Xenobio. Metab. Dispos.

Review
Metabolism of Tacrolimus (FK506) and Recent Topics in Clinical Pharmacokinetics