Exposure of Fexofenadine, but Not Pseudoephedrine, Is Markedly Decreased by Green Tea Extract in Healthy Volunteers

Abstract

Green tea (GT) alters the disposition of a number of drugs, such as nadolol and lisinopril. However, it is unknown whether GT affects disposition of hydrophilic anti-allergic drugs. The purpose of this study was to investigate whether pharmacokinetics of fexofenadine and pseudoephedrine are affected by catechins, major GT components. A randomized, open, 2-phase crossover study was conducted in 10 healthy Japanese volunteers. After overnight fasting, subjects were simultaneously administered fexofenadine (60 mg) and pseudoephedrine (120 mg) with an aqueous solution of green tea extract (GTE) containing (-)-epigallocatechin gallate (EGCG) of ~ 300 mg or water (control). In vitro transport assays were performed using HEK293 cells stably expressing organic anion transporting polypeptide (OATP)1A2 to evaluate the inhibitory effect of EGCG on OATP1A2-mediated fexofenadine transport. In the GTE phase, the area under the plasma concentration-time curve and the amount excreted unchanged into urine for 24 hours of fexofenadine were significantly decreased by 70% (P < 0.001) and 67% (P < 0.001), respectively, compared with control. There were no differences in time to maximum plasma concentration and the elimination half-life of fexofenadine between phases. Fexofenadine was confirmed to be a substrate of OATP1A2, and EGCG (100 and 1,000 μM) and GTE (0.1 and 1 mg/mL) inhibited OATP1A2-mediated uptake of fexofenadine. On the contrary, the concomitant administration of GTE did not influence the pharmacokinetics of pseudoephedrine. These results suggest that intake of GT may result in a markedly reduced exposure of fexofenadine, but not of pseudoephedrine, putatively by inhibiting OATP1A2-mediated intestinal absorption.

Figure 1

Plasma concentration profile of fexofenadine after oral administration of fexofenadine (60 mg) with 150 mL of an aqueous solution of (−)‐epigallocatechin gallate (EGCG)‐concentrated green tea extract (○), or water (●) in 10 healthy volunteers. Data are expressed as the arithmetic mean ± SD. The inset is the log‐concentration vs. time profile.

Figure 2

Urinary excretion of fexofenadine after oral administration of fexofenadine (60 mg) with 150 mL of an aqueous solution of (−)‐epigallocatechin gallate (EGCG)‐concentrated green tea extract (○), or water (●) in 10 healthy volunteers. (a) Cumulative urinary excretion (mg) of fexofenadine over 24 hours after administration, (b) % of dose, and (c) renal clearance (CL_R) of fexofenadine. Data are expressed as the arithmetic mean ± SD. **, P < 0.01 with respect to water phase. GTE, green tea extract.

Figure 3

Plasma concentration profile of pseudoephedrine after oral administration of pseudoephedrine (120 mg) with 150 mL of an aqueous solution of (−)‐epigallocatechin gallate (EGCG)‐concentrated green tea extract (○), or water (●) in 10 healthy volunteers. Data are expressed as the arithmetic mean ± SD. The inset is the log‐concentration vs. time profile.

Figure 4

Urinary excretion of pseudoephedrine after oral administration of pseudoephedrine (120 mg) with 150 mL of an aqueous solution of (−)‐epigallocatechin gallate (EGCG)‐concentrated green tea extract (GTE; ○), or water (●) in 10 healthy volunteers. (a) Cumulative urinary excretion (mg) of pseudoephedrine over 24 hours after administration, (b) percent of dose, and (c) renal clearance (CL_R) of pseudoephedrine. Data are expressed as the arithmetic mean ± SD.

Figure 5

In vitro uptake assays of fexofenadine in HEK‐OATP1A2 cells or sulfobromophthalein (BSP) in HEK‐OATP2B1 cells (black bars), and in the respective HEK control cells (PQX) for OATP1A2 or (VC) for OATP2B1 (white bars). Cellular accumulation of 10 μM fexofenadine at pH 7.3 (a), or 1 μM BSP at pH 7.3 (b) and pH 6.3 (c) after 10 minutes incubation was measured by liquid chromatography–tandem mass spectrometry (LC–MS/MS) (fexofenadine) or liquid scintillation counting (BSP) in the presence or absence of (−)‐epigallocatechin gallate (EGCG at 100 and 1,000 μM) or EGCG‐concentrated green tea extract (GTE at 0.1 and 1 mg/mL) used in the clinical study. Data are presented as mean ± SEM. (n = 6). **P < 0.01, vs. uptake into HEK293 control cells (PQX or VC); ^## P < 0.01, vs. uptake into HEK293‐OATP1A2 or HEK‐OATP2B1 cells without inhibitors.