Evaluation of a potential pharmacokinetic interaction between green tea and digoxin

P-glycoprotein, a member of the ATP-binding cassette family of transporters, is an efflux transporter that transports a wide range of drugs and hence has significant effects on the disposition of its substrates. A number of drug-drug interactions have been attributed to modulation of P-gp function in different tissues. Digoxin is a P-gp substrate that is not metabolized and is almost exclusively transported by P-gp. It is considered a sensitive and specific probe and is recommended by the U.S. FDA for in vitro and in vivo assessment of P-gp transport function. Green tea is a widely used dietary ingredient and herbal supplement worldwide. Polyphenols in green tea have been shown to modulate P-gp function in vitro and hence the possibility of clinically significant DDI when green tea is co-administered with P-gp substrates needs to be investigated. This study was conducted to study the effects of green tea on P-gp function, in humans, using digoxin as a P-gp probe. To compare digoxin pharmacokinetics with and without the co-administration of green tea, a cross-over design was employed. Eight healthy volunteers were enrolled in and completed the two-phase study. Plasma samples for determination of digoxin concentrations were collected for the first 4 hrs in both phases. A pharmacokinetic non-compartmental analysis was performed to derive digoxin pharmacokinetic (PK) parameters (area under the digoxin plasma concentration-time curve AUC(0-4) , maximum plasma concentration Cmax , and time for maximum plasma concentration tmax ). In addition, digoxin pharmacodynamic (PD) parameters (area under the effect curve for PR interval AUECPR-24 , area under the effect curve for heart rate AUECHR-24 , maximum change in PR interval from baseline within 24 hrs MAXPR-24 , and maximum change in heart rate from baseline within 24 hrs MAXHR-24 ) were derived from electrocardiographic measurements collected during each of the two phases. Digoxin PK and PD parameters from each of eight subjects were compared between the two phases using a paired Student\u27s t-test or Wilcoxon signed rank test (for non-normally distributed data) to test for any significant differences associated with co-administration of green tea. Digoxin median Cmax and tmax values were similar in both water and green tea phases whereas mean AUC(0-4) was slightly, but not statistically significantly, higher on the water phase (p=0.148). The mean (±SD) AUECPR-24 values were 4043 (±704) and 3907 (±660) msec*hr for water and green tea phases (p=0.064). Similarly, the mean AUECHR-24 was similar for the two phases (1704±129 and 1670±187 bpm.hr, respectively, p=0.42). The mean (±SD) Max PR-24 for the water phase (11.1±8.3) was more than double that for the green tea phase (5.0±5.7) although the difference was not statistically significant (p=0.124). Conversely, the median MaxHR-24 for the water phase (5.5, range=0-44) was less than half that for the green tea phase (12, range=10-45) but the difference did not reach statistical significance (p=0.058). Other than few asymptomatic and reversible episodes of bradycardia and prolonged PR intervals, no subjects experienced any adverse effects of the co-administration of digoxin and green tea. In conclusion, acute green tea administration does not cause any significant changes in digoxin pharmacokinetics or digoxin mediated cardiac electrocardiographic effects. Co-administration of green tea and digoxin (0.5 mg) is well tolerated and not associated with any significant adverse effects. Consequently, co-administration of green tea (at amounts similar to those used in this study) with P-gp substrates is not expected to lead to significant changes in substrate exposure and hence the combination can be considered safe