Misaka S, Yatabe J, Müller F, et al. Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects. Clin Pharmacol Ther. 2014;95(4):432-438.

Given the global popularity of green tea (Camellia sinensis) as a beverage and herbal supplement,¹ concomitant use of green tea and pharmaceuticals is likely. Most food-drug interactions are attributed to the inhibition or induction of cytochrome P450 (CYP) 3A liver enzymes and/or intestinal transporters such as P-glycoprotein (P-gp) and organic anion transporting polypeptides (OATPs).^2,3 Although green tea is thought to cause negligible or minor CYP-mediated drug interactions, in vitro studies suggest that its constituent catechins, including epigallocatechin-3-gallate (EGCG), may inhibit P-gp,^4,5 and that EGCG and epicatechin-3-gallate (ECG) inhibit OATP1A2- and OATP2B1-mediated uptake.⁶ Nadolol, a nonselective beta-adrenergic receptor blocker used to treat hypertension, is not metabolized by enzymes such as CYP3A⁷; however, studies suggest that green tea consumption may change the pharmacokinetics of nadolol by inhibiting P-gp- or OATP-mediated transport into the intestine. This randomized, placebo-controlled, crossover study evaluated the effects of green tea consumption on the pharmacokinetics and pharmacodynamics of nadolol in healthy subjects.

The study included 10 healthy, nonsmoking Japanese subjects (8 males and 2 females). They were aged 20-30 years, with a body mass index of 18.3-23.9 kg/m². Subjects ingested 700 mL/day of the assigned treatment for 14 days. On day 15, they consumed a single dose of NADIC (30 mg nadolol) (Dainippon Sumitomo Pharma; Osaka, Japan), along with 350 mL of the study beverage. Thirty minutes later, the subjects consumed another 350 mL of the beverage. There was a 2-week washout period between the 2 treatment arms. The placebo beverage was water. The active treatment was the commercial green tea beverage Healthya^® (Kao Corporation; Tokyo, Japan), which contained 80 μg/mL epicatechin (EC), 240 μg/mL epigallocatechin (EGC), 130 μg/mL ECG, and 460 μg/mL EGCG. Therefore, by drinking 700 mL/day green tea, the daily intake of EC, EGC, ECG and EGCG was 56, 168, 91, and 322 mg, respectively. The laboratory and method used to determine the green tea content were not reported.

In each study arm, blood samples were collected and pharmacodynamic parameters, pulse rate, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were recorded before nadolol administration and after 0.5, 1, 2, 3, 4, 6, 8, 24, and 48 hours; urine was collected at 0-8, 8-24, and 24-48 hours.

The green tea treatment markedly reduced the plasma concentration of nadolol compared with the water intervention. The maximum plasma concentration (C_max) and area under the curve (AUC) of nadolol decreased by 85.3% (P=0.007) and 85% (P<0.001), respectively. The T_max of nadolol occurred earlier after green tea consumption compared to water (P=0.013).

Urinary excretion of nadolol was markedly reduced by 81.6% during the green tea phase compared with the water phase. No significant difference was observed in the renal clearance of nadolol during the washout between the 2 study interventions. In the water phase, nadolol lowered pulse rate by 20%, SBP by 12%, and DBP by 11%. Green tea tended to reduce the pharmacodynamic responses to nadolol for these parameters, but only nadolol's effects on SBP (P=0.042) were significantly reduced.

The authors conducted in vitro experiments to determine the involvement of OATP1A2 and OATP2B1 in the cellular accumulation of nadolol and the effects of green tea and its catechins on OATP-mediated nadolol transport. The uptake of nadolol was assessed using OATP1A2- and OATP2B1-expressing human embryonic kidney (HEK) 293 cells and vector-transfected cells. [³H] nadolol uptake assays in HEK293 cells suggested that nadolol was a substrate of OATP1A2 but not of OATP2B1, and that EGCG and green tea significantly inhibited OATP1A2-mediated uptake of nadolol.

In this study, the concomitant administration of nadolol with green tea after ingestion of green tea for 14 days significantly changed the pharmacokinetics and the blood pressure-lowering effect of nadolol in healthy subjects. The authors conclude, "Although further studies are required …, the current data suggest that patients treated with nadolol should avoid drinking green tea."

This study was limited by the small age- and gender-biased sample size, and the lack of control for pharmacogenetic variability. Any one of these factors may significantly affect the outcomes.

―Shari Henson

References

¹Graham HN. Green tea composition, consumption, and polyphenol chemistry. Prev Med. 1992;21(3):334-350.

²Dolton MJ, Roufogalis BD, McLachlan AJ. Fruit juices as perpetrators of drug interactions: the role of organic anion-transporting polypeptides. Clin Pharmacol Ther. 2012;92(5):622-630.

³König J, Müller F, Fromm MF. Transporters and drug-drug interactions: important determinants of drug disposition and effects. Pharmacol Rev. 2013;65(3):944-966.

⁴Jodoin J, Demeule M, Beliveau R. Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols. Biochim Biophys Acta. 2002;1542(1-3):149-159.

⁵Qian F, Wei D, Zhang Q, Yang S. Modulation of P-glycoprotein function and reversal of multidrug resistance by (–)-epigallocatechin gallate in human cancer cells. Biomed Pharmacother. 2005;59(3):64-69.

⁶Roth M, Timmermann BN, Hagenbuch B. Interactions of green tea catechins with organic anion-transporting polypeptides. Drug Metab Dispos. 2011;39(5):920-926.