Lack of pharmacokinetic interaction between fluvastatin and green tea in healthy volunteers
The objective of this study is to assess the effects of green tea and its major catechin component, (−)-epigallocatechin gallate (EGCG), on CYP2C9-mediated substrate metabolism in vitro, and the pharmacokinetics of fluvastatin in healthy volunteers.
The metabolism of diclofenac and fluvastatin in human recombinant CYP2C9 was investigated in the presence of EGCG. In a randomized three-phase crossover study, 11 healthy volunteers ingested a single 20-mg dose of fluvastatin with green tea extract (GTE), containing 150 mg of EGCG, along with water (300 mL), brewed green tea (300 mL), or water (300 mL) after overnight fasting. Plasma concentrations of fluvastatin and EGCG were measured by ultra-performance liquid chromatography with fluorescence detection and a single mass spectrometer.
EGCG inhibited diclofenac 4′-hydroxylation and fluvastatin degradation with IC50 of 2.23 and 48.04 μM, respectively. Brewed green tea used in the clinical study also dose-dependently inhibited the metabolism of diclofenac and fluvastatin in vitro. However, no significant effects of GTE and brewed green tea were observed in plasma concentrations of fluvastatin. The geometric mean ratios with 90% CI for area under the plasma concentration–time curve (AUC0–∞) of fluvastatin were 0.993 (0.963–1.024, vs. brewed green tea) and 0.977 (0.935–1.020, vs. GTE).
Although in vitro studies indicated that EGCG and brewed green tea produce significant inhibitory effects on CYP2C9 activity, the concomitant administration of green tea and fluvastatin in healthy volunteers did not influence the pharmacokinetics of fluvastatin.
KeywordsCYP2C9 Diclofenac (−)-Epigallocatechin gallate Fluvastatin Green tea Pharmacokinetics
We thank Dr. Yoshinori Tanino, Dr. Xintao Wang, Ms. Ayaka Ushigome, and Mr. Rintaro Miyo for their excellent technical support. This work was supported partly by the Honjo International Scholarship Foundation.
Misaka, Abe, Shikama, Onoue, Yabe, and Kimura participated in the research design. Misaka, Abe, Sato, and Ono conducted the experiments and clinical study. Misaka, Abe, Sato, Onoue, and Kimura performed the data analysis. Misaka, Abe, Shikama, Onoue, Yabe, and Kimura wrote or contributed to the writing of the manuscript.
Compliance with ethical standards
The authors declared that they have no conflicts of interest.
- 3.Misaka S, Kawabe K, Onoue S, Werba JP, Giroli M, Tamaki S, Kan T, Kimura J, Watanabe H, Yamada S (2013) Effects of green tea catechins on cytochrome P450 2B6, 2C8, 2C19, 2D6 and 3A activities in human liver and intestinal microsomes. Drug Metab Pharmacokinet 28(3):244–249. https://doi.org/10.2133/dmpk.DMPK-12-RG-101 CrossRefPubMedGoogle Scholar
- 10.Knop J, Misaka S, Singer K, Hoier E, Müller F, Glaeser H, König J, Fromm MF (2015) Inhibitory effects of green tea and (−)-epigallocatechin gallate on transport by OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K and P-glycoprotein. PLoS One 10(10):e0139370. https://doi.org/10.1371/journal.pone.0139370 CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Misaka S, Yatabe J, Müller F, Takano K, Kawabe K, Glaeser H, Yatabe MS, Onoue S, Werba JP, Watanabe H, Yamada S, Fromm MF, Kimura J (2014) Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects. Clin Pharmacol Ther 95(4):432–438. https://doi.org/10.1038/clpt.2013.241 CrossRefPubMedGoogle Scholar
- 16.Netsch MI, Gutmann H, Luescher S, Brill S, Schmidlin CB, Kreuter MH, Drewe J (2005) Inhibitory activity of a green tea extract and some of its constituents on multidrug resistance-associated protein 2 functionality. Planta Med 71(2):135–141. https://doi.org/10.1055/s-2005-837780 CrossRefPubMedGoogle Scholar
- 20.Werba JP, Misaka S, Giroli MG, Yamada S, Cavalca V, Kawabe K, Squellerio I, Laguzzi F, Onoue S, Veglia F, Myasoedova V, Takeuchi K, Adachi E, Inui N, Tremoli E, Watanabe H (2015) Overview of green tea interaction with cardiovascular drugs. Curr Pharm Des 21(9):1213–1219. https://doi.org/10.2174/1381612820666141013135045 CrossRefPubMedGoogle Scholar
- 21.Chow HH, Hakim IA, Vining DR, Crowell JA, Cordova CA, Chew WM, Xu MJ, Hsu CH, Ranger-Moore J, Alberts DS (2006) Effects of repeated green tea catechin administration on human cytochrome P450 activity. Cancer Epidemiol Biomark Prev 15(12):2473–2476. https://doi.org/10.1158/1055-9965.EPI-06-0365 CrossRefGoogle Scholar
- 22.Chow HH, Hakim IA, Vining DR, Crowell JA, Ranger-Moore J, Chew WM, Celaya CA, Rodney SR, Hara Y, Alberts DS (2005) Effects of dosing condition on the oral bioavailability of green tea catechins after single-dose administration of Polyphenon E in healthy individuals. Clin Cancer Res 11(12):4627–4633. https://doi.org/10.1158/1078-0432.CCR-04-2549 CrossRefPubMedGoogle Scholar
- 23.Tse FL, Jaffe JM, Troendle A (1992) Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers. J Clin Pharmacol 32(7):630–638. https://doi.org/10.1002/j.1552-4604.1992.tb05773.x CrossRefPubMedGoogle Scholar
- 28.Kirchheiner J, Kudlicz D, Meisel C, Bauer S, Meineke I, Roots I, Brockmöller J (2003) Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (−)-3S,5R-fluvastatin and (+)-3R,5S-fluvastatin in healthy volunteers. Clin Pharmacol Ther 74(2):186–194. https://doi.org/10.1016/S0009-9236(03)00121-8 CrossRefPubMedGoogle Scholar
- 32.Noé J, Portmann R, Brun ME, Funk C (2007) Substrate-dependent drug-drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metab Dispos 35(8):1308–1314. https://doi.org/10.1124/dmd.106.012930 CrossRefPubMedGoogle Scholar
- 33.Varma MV, Rotter CJ, Chupka J, Whalen KM, Duignan DB, Feng B, Litchfield J, Goosen TC, El-Kattan AF (2011) pH-sensitive interaction of HMG-CoA reductase inhibitors (statins) with organic anion transporting polypeptide 2B1. Mol Pharm 8(4):1303–1313. https://doi.org/10.1021/mp200103h CrossRefPubMedGoogle Scholar
- 37.Misaka S, Kawabe K, Onoue S, Werba JP, Giroli M, Kimura J, Watanabe H, Yamada S (2013) Development of rapid and simultaneous quantitative method for green tea catechins on the bioanalytical study using UPLC/ESI-MS. Biomed Chromatogr 27(1):1–6. https://doi.org/10.1002/bmc.2740 CrossRefPubMedGoogle Scholar
- 38.Masuda N, Akasaka I, Suzuki J, Fujino A, Ohtawa M, Nakaya N, Goto Y, Takahashi N, Sekino H, Amamoto T, Urae A, Maeda A, Irie S (1995) Phase I study of fluvastatin, a new synthetic HMG-CoA reductase inhibitor—pharmacokinetics of fluvastatin in healthy male volunteers after single and multiple oral administration. Rinsho Iyaku 11:65–81Google Scholar
- 41.Zhou Q, Ruan ZR, Yuan H, Zeng S (2012) CYP2C9*3(1075A>C), MDR1 G2677T/A and MDR1 C3435T are determinants of inter-subject variability in fluvastatin pharmacokinetics in healthy Chinese volunteers. Arzneimittelforschung 62(11):519–524. https://doi.org/10.1055/s-0032-1323696 CrossRefPubMedGoogle Scholar
- 42.Birmingham BK, Bujac SR, Elsby R, Azumaya CT, Wei C, Chen Y, Mosqueda-Garcia R, Ambrose HJ (2015) Impact of ABCG2 and SLCO1B1 polymorphisms on pharmacokinetics of rosuvastatin, atorvastatin and simvastatin acid in Caucasian and Asian subjects: a class effect? Eur J Clin Pharmacol 71(3):341–355. https://doi.org/10.1007/s00228-014-1801-z CrossRefPubMedGoogle Scholar