Inhibition effect of epigallocatechin-3-gallate on the pharmacokinetics of calcineurin inhibitors, tacrolimus, and cyclosporine A, in rats

ABSTRACT

Background

Epigallocatechin-3-gallate (EGCG) is the most biologically active catechin of green tea. Tacrolimus (TAC) and cyclosporine A (CsA) are immunosuppressive agents commonly used in clinical organ transplantation. The present study investigated the effect of EGCG on the pharmacokinetics of TAC and CsA in rats and its underlying mechanisms.

Research design and methods

Either TAC or CsA was administered to rats intravenously or orally with or without concomitant EGCG. Polymerase Chain Reaction and Western Blot were used to determine the effect of EGCG on drug-metabolizing enzymes (DMEs), drug transporters (DTs) and nuclear receptors (NRs).

Results

The C_max and AUC of TAC were reduced, and V/F and CL/F of TAC were enhanced after co-administration of EGCG. EGCG increased the Cmax, AUC of CsA at 3 ~ 30 mg∙kg-1 dosages, while decreased those parameters at the dosage of 100 mg∙kg-1. EGCG inhibited the mRNA and protein expressions of DMEs and DTs, such as CYP3A1, A2, UGT1A1, Mdr1 and Mrp2, but upregulated the expressions of Car, Pxr and Fxr.

Conclusions

These results revealed consumption of high dose EGCG may cause a significant alteration in pharmacokinetics of TAC and distribution/elimination profiles of CsA through the regulation of DMEs, DTs and NRs.

KEYWORDS:

• Tacrolimus
• cyclosporine A
• epigallocatechin-3-gallate
• drug-metabolizing enzymes
• drug transporters
• nuclear receptor

Author contributions

Xixi Huang, Rui Zhang, Yani Liu and Shaojun Shi designed the study. Xixi Huang, Tingyu Yang, Ye Wei performed all the animal experiments. Rui Zhang, Chunxiao Yang and Jiani Zhou performed the Real-time PCR and western blotting. Xixi Huang processed the data and performed statistical analysis. Xixi Huang and Rui Zhang wrote the original draft preparation. Yani Liu and Shaojun Shi revised the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was financially supported by National Natural Science Foundation of China (81874326), Chinese Medicine Research Project of Health Commission of Hubei Province (ZY2019Z004); National Key R&D Program of China (2017YFC0909900).