Interaction of green tea polyphenol epigallocatechin-3-gallate with sunitinib: potential risk of diminished sunitinib bioavailability

Abstract

Sunitinib, a novel oral multi-targeted tyrosine kinase inhibitor for patients with metastatic renal cell carcinoma (mRCC) and advanced gastrointestinal stromal tumor, has a good prospect for clinical application and is being investigated for the potential therapy of other tumors. We observed the phenomenon that drinking tea interfered with symptom control in an mRCC patient treated with sunitinib and speculated that green tea or its components might interact with sunitinib. This study was performed to investigate whether epigallocatechin-3-gallate (EGCG), the major constituent of green tea, interacted with sunitinib. The interaction between EGCG and sunitinib was examined in vitro and in vivo. (1)H nuclear magnetic resonance ((1)H-NMR) spectroscopy and mass spectrometry (MS) were used to analyze the interaction between these two molecules and whether a new compound was formed. Solutions of sunitinib and EGCG were intragastrically administered to rats to investigate whether the plasma concentrations of sunitinib were affected by EGCG. In this study, we noticed that a precipitate was formed when the solutions of sunitinib and EGCG were mixed under both neutral and acidic conditions. (1)H-NMR spectra indicated an interaction between EGCG and sunitinib, but no new compound was observed by MS. Sticky semisolid contents were found in the stomachs of sunitinib and EGCG co-administrated mice. The AUC(0-∞) and C (max) of plasma sunitinib were markedly reduced by co-administration of EGCG to rats. Our study firstly showed that EGCG interacted with sunitinib and reduced the bioavailability of sunitinib. This finding has significant practical implications for tea-drinking habit during sunitinib administration.

Effect of P-Glycoprotein and Breast Cancer Resistance Protein Inhibition on the Pharmacokinetics of Sunitinib in Rats

“…Several reports have indicated pharmacokinetic interaction between sunitinib and drugs (Di Gion et al, 2011) or foods Ge et al, 2011;van Erp et al, 2011). In particular, a clinical study demonstrated that coadministration of rifampicin, an inducer of CYP3A4, significantly decreased systemic exposure to sunitinib (Di Gion et al, 2011).…”

Green tea polyphenol epigallocatechin-3-gallate (EGCG) as adjuvant in cancer therapy

“…Reduced bioavailability of the anticancer drug sunitinib has been recently related to co-administration with EGCG. 28 These observations show the need to conduct further studies to ascertain the interaction between EGCG and different anticancer drugs, for each particular type and stage of cancer. The possibility of antagonistic interactions must be taken into account in the development of new cancer therapy strategies based on drug-EGCG cotreatments.…”

“…27,28 [ Increase; Y decrease; [Y modulation; AMPK, AMP-activated protein kinase; AR, androgen receptor; ATO, arsenic trioxide; BCRP, breast cancer resistant protein; CBR1, carbonyl reductase 1; DPD, dihydropyrimidine dehydrogenase; ER, estrogen receptor; GRP78, glucose-regulated protein 78; MDR1, multidrug resistance protein; P-gP, Pglycoprotein; ROS, reactive oxygen species; TSA, trichostatin-A.…”

Untitled

“…The values of C max and AUC of CYP3A and P-gp substrates, diltiazem, verapamil, tamoxifen, simvastatin, and nicardipine were increased after rats were exposed to EGCG, suggesting that EGCG might inhibit CYP3A and/or P-gp activities [28-30, 33, 35]. However, the C max and AUC of other CYP3A4 substrates (e.g., quetiapine, sunitinib) were reduced in rats administered GTE or EGCG [27,36]. GTE decreased the C max and AUC of clozapine in rats, ostensibly due to the metabolic induction of CYP1A2 [32].…”