Green Tea Alters Bile Acid Micellar Solubility of Raloxifene

Abstract

Green tea is a popular botanical natural product, and its consumption has been associated with pharmacokinetic natural product‐drug interactions (NP‐DIs). Unpublished clinical data show that acute and chronic oral administration of green tea decreased the systemic exposure of raloxifene in healthy subjects. These clinical data indicate an intestinal interaction, although the mechanism for reduced absorption and systemic exposure is not known. NP‐mediated modulation of drug solubility in the intestinal lumen is an area of increasing interest and concern. Intestinal bile acids can enhance the absorption of hydrophobic compounds by micellar solubilization, and raloxifene is a Biopharmaceutic Drug Disposition Classification System (BDDCS) class 2 drug with poor water solubility. We hypothesize that green tea reduces intestinal absorption of raloxifene through decreased micellar solubility. To investigate this interaction, bile acid mixed micelles were prepared and incubated with raloxifene, green tea extract (GTE), (‐)‐epigallocatechin gallate EGCG, and a combination of raloxifene with GTE or EGCG. The size of the micelles was determined by dynamic light scattering and raloxifene quantification was determined by UPLC‐MS/MS. Raloxifene did not affect micelle diameter (micelle alone: 63.2 ± 5.6 nm, micelle with raloxifene 76.0 ± 5.8). In contrast, micelle diameter increased after incubation with GTE (416 ± 150.3 nm), EGCG (300.9 ± 173 nm), raloxifene + GTE (451 ± 164.2 nm), and raloxifene + EGCG (294.8 ± 303 nm). The micellar solubility of raloxifene was decreased by ~80% after incubation with GTE, whereas EGCG produced inconsistent results. These data suggest GTE decreased the micellar solubility of raloxifene and may play a role in the observed green tea‐raloxifene intestinal interaction.