# Berberine-Mediated BCRP Inhibition Enhances Systemic Exposure of Rhein: A Study to Unravel the Pharmacokinetic Basis of Synergy in Da-Huang-Xiao-Shi Decoction

## TL;DR

This study explains how a traditional Chinese medicine formula improves liver protection by increasing the absorption of a key compound through transporter inhibition.

## Contribution

The study identifies berberine's role in inhibiting BCRP to enhance rhein absorption, revealing a pharmacokinetic basis for herbal synergy.

## Key findings

- DHXSD provided stronger hepatoprotection than Rheum palmatum alone.
- Berberine inhibited BCRP, increasing rhein's systemic exposure by about 2-fold.
- Geniposide had minimal effect on BCRP or rhein absorption.

## Abstract

Background/Objectives: Cholestasis is a clinically intractable liver disorder. Da-Huang-Xiao-Shi Decoction (DHXSD), a classic traditional Chinese medicine formula, demonstrates notable efficacy, yet the mechanistic basis for its multi-herb synergy remains unclear. The purpose of this study was to decipher the pharmacokinetic interaction underlying the synergy of DHXSD. Methods: A cholestatic rat model was established in male Sprague Dawley rats. Hepatoprotective efficacy was evaluated, and the pharmacokinetics of anthraquinones were profiled. Key interaction mechanisms were investigated using the everted intestinal sac model, the breast cancer resistance protein (BCRP)-overexpressing MDCKII cells, and molecular docking simulations. Results: DHXSD provided significantly stronger hepatoprotection than its principal herb Rheum palmatum L. (DaHuang, DH) alone. This enhanced efficacy correlated with an approximate 2-fold increase in the systemic exposure of rhein compared to DH monotherapy. We identified berberine from Phellodendron amurense Rupr. (Huang Bo, HB) as the key synergist, which potently inhibited the BCRP efflux transporter, thereby enhancing rhein absorption. In contrast, geniposide from Gardenia jasminoides Ellis (Zhi Zi, ZZ) showed minimal effects. Conclusions: This work elucidates a concrete, transporter-mediated pharmacokinetic interaction as the core mechanism underlying herbal synergy in DHXSD. Our findings offer a rational strategy—targeted efflux transporter modulation—for improving the oral bioavailability of challenging drug molecules.