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Letters to the Editor Response to “The Effect of Green Tea With Exceptionally High Catechin Content on Nadolol Plasma Concentration” S Misaka1,2, J Yatabe1, F Müller2, K Takano1, H Glaeser2, MS Yatabe1, S Onoue3, JP Werba4, H Watanabe5, S Yamada3, MF Fromm2 and J Kimura1 To the Editor: We appreciate the opportunity to respond to the letter “The Effect of Green Tea With Exceptionally High Catechin Content on Nadolol Plasma Concentration,” by Ide et al.1 In their letter, the authors commented on the green tea (GT) content used in our clinical trial as well as on our study design.2 Our study design was based on a prospective cohort study that reported that >50 and 15% of Japanese aged over 40 years consume four to nine cups and more than nine cups, respectively, of GT daily.3 The authors of that article estimated that 10 cups of GT contain 300–400 mg of (–)-epigallocatechin gallate (EGCG). Accordingly, we decided to use ~300 mg EGCG per day in our study. To minimize the interindividual and interday variations in the consumption of catechins, a commercially available bottled GT was used as a standardized source of catechins, for which we determined catechin concentrations before
beginning the clinical study. Ide et al. state correctly that the GT used in our study contains several times higher catechin concentrations than those in other bottled GTs sold in Japan. However, the catechin concentration in the GT used in our study is comparable to that in brewed GT (97–239 mg/dl)4 or dietary supplements of catechins. We therefore disagree with the comment by Ide et al. that we used GT with exceptionally high catechin content. Moreover, we point out that guidelines on the investigation of drug interactions in clinical studies recommend aiming at worst-case scenarios, i.e., to use “the highest generally recommended dose under therapeutic (steady state) conditions” of a perpetrator drug (or, in this case, GT dose and catechin concentrations) so as to reveal the maximal extent of an interaction.5 These guidelines also include recommendations regarding time-dependent interactions, for example, that the interaction effect be investigated “at the time-point where the … inhibition effect is at or near its maximum.” Therefore, in our study, GT was administered concomitantly with nadolol to increase the likelihood and extent of the interaction. Given the current guidelines on investigation of drug interactions, it would have been difficult to justify the use of another GT with lower catechin concentrations or another design. We hope that our findings regarding the GT–nadolol interaction will stimulate further research in this field, e.g., regarding the impact of GT on the pharmacokinetics and effects of other drugs.
Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 6 | JUNE 2014
CONFLICT OF INTEREST M.F.F. reported receiving personal compensation for expert testimony from Boehringer Ingelheim Pharma and payments for lectures from Bayer-Schering Pharma, Sanofi-Aventis Deutschland, and Merck KGaA. M.F.F.’s institution received compensation from Merck KGaA and Sanofi-Aventis Deutschland for commissioned research performed by his group and from Gilead for supplies for in vitro studies. The other authors declared no conflict of interest. © 2014 ASCPT
1. Ide, K., Park, M. & Yamada, H. The effect of green tea with exceptionally high catechin content on nadolol plasma concentration. Clin. Pharmacol. Ther. 95, 565 (2014). 2. Misaka, S. et al. Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects. Clin. Pharmacol. Ther. 95, 432–438 (2014). 3. Imai, K., Suga, K. & Nakachi, K. Cancerpreventive effects of drinking green tea among a Japanese population. Prev. Med. 26, 769–775 (1997). 4. Mizukami, Y., Sawai, Y. & Yamaguchi, Y. Simultaneous analysis of catechins, gallic acid, strictinin, and purine alkaloids in green tea by using catechol as an internal standard. J. Agric. Food Chem. 55, 4957–4964 (2007). 5. European Medicines Agency. Guideline on the Investigation of Drug Interactions. (2012).
1Department of Pharmacology, School of Medicine, Fukushima Medical University, Fukushima, Japan; 2Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-AlexanderUniversität Erlangen-Nürnberg, Erlangen, Germany; 3Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; 4Centro Cardiologico Monzino IRCCS, Milan, Italy; 5Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan. Correspondence: S Misaka ([email protected])
advance online publication 16 April 2014. doi:10.1038/clpt.2014.61
589
nature publishing group
Letters to the Editor Response to “The Effect of Green Tea With Exceptionally High Catechin Content on Nadolol Plasma Concentration” S Misaka1,2, J Yatabe1, F Müller2, K Takano1, H Glaeser2, MS Yatabe1, S Onoue3, JP Werba4, H Watanabe5, S Yamada3, MF Fromm2 and J Kimura1 To the Editor: We appreciate the opportunity to respond to the letter “The Effect of Green Tea With Exceptionally High Catechin Content on Nadolol Plasma Concentration,” by Ide et al.1 In their letter, the authors commented on the green tea (GT) content used in our clinical trial as well as on our study design.2 Our study design was based on a prospective cohort study that reported that >50 and 15% of Japanese aged over 40 years consume four to nine cups and more than nine cups, respectively, of GT daily.3 The authors of that article estimated that 10 cups of GT contain 300–400 mg of (–)-epigallocatechin gallate (EGCG). Accordingly, we decided to use ~300 mg EGCG per day in our study. To minimize the interindividual and interday variations in the consumption of catechins, a commercially available bottled GT was used as a standardized source of catechins, for which we determined catechin concentrations before
beginning the clinical study. Ide et al. state correctly that the GT used in our study contains several times higher catechin concentrations than those in other bottled GTs sold in Japan. However, the catechin concentration in the GT used in our study is comparable to that in brewed GT (97–239 mg/dl)4 or dietary supplements of catechins. We therefore disagree with the comment by Ide et al. that we used GT with exceptionally high catechin content. Moreover, we point out that guidelines on the investigation of drug interactions in clinical studies recommend aiming at worst-case scenarios, i.e., to use “the highest generally recommended dose under therapeutic (steady state) conditions” of a perpetrator drug (or, in this case, GT dose and catechin concentrations) so as to reveal the maximal extent of an interaction.5 These guidelines also include recommendations regarding time-dependent interactions, for example, that the interaction effect be investigated “at the time-point where the … inhibition effect is at or near its maximum.” Therefore, in our study, GT was administered concomitantly with nadolol to increase the likelihood and extent of the interaction. Given the current guidelines on investigation of drug interactions, it would have been difficult to justify the use of another GT with lower catechin concentrations or another design. We hope that our findings regarding the GT–nadolol interaction will stimulate further research in this field, e.g., regarding the impact of GT on the pharmacokinetics and effects of other drugs.
Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 6 | JUNE 2014
CONFLICT OF INTEREST M.F.F. reported receiving personal compensation for expert testimony from Boehringer Ingelheim Pharma and payments for lectures from Bayer-Schering Pharma, Sanofi-Aventis Deutschland, and Merck KGaA. M.F.F.’s institution received compensation from Merck KGaA and Sanofi-Aventis Deutschland for commissioned research performed by his group and from Gilead for supplies for in vitro studies. The other authors declared no conflict of interest. © 2014 ASCPT
1. Ide, K., Park, M. & Yamada, H. The effect of green tea with exceptionally high catechin content on nadolol plasma concentration. Clin. Pharmacol. Ther. 95, 565 (2014). 2. Misaka, S. et al. Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects. Clin. Pharmacol. Ther. 95, 432–438 (2014). 3. Imai, K., Suga, K. & Nakachi, K. Cancerpreventive effects of drinking green tea among a Japanese population. Prev. Med. 26, 769–775 (1997). 4. Mizukami, Y., Sawai, Y. & Yamaguchi, Y. Simultaneous analysis of catechins, gallic acid, strictinin, and purine alkaloids in green tea by using catechol as an internal standard. J. Agric. Food Chem. 55, 4957–4964 (2007). 5. European Medicines Agency. Guideline on the Investigation of Drug Interactions. (2012).
1Department of Pharmacology, School of Medicine, Fukushima Medical University, Fukushima, Japan; 2Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-AlexanderUniversität Erlangen-Nürnberg, Erlangen, Germany; 3Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; 4Centro Cardiologico Monzino IRCCS, Milan, Italy; 5Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan. Correspondence: S Misaka ([email protected])
advance online publication 16 April 2014. doi:10.1038/clpt.2014.61
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