High hepatic exposure to ferulic acid, ligustilide, and ligustrazine in Chuanxiong Rhizome is associated with transporter-mediated active uptake

Hantian Tan¹, Guosheng Zou^2,*

1. Department of pharmacy, The First Affiliated Hospital of Guangzhou University of Chinese Medicine; Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou 510000, Guangdong, China.
2. Department of pharmacy, Guangdong Second Provincial General Hospital, Guangzhou 510000, Guangdong, China.

*Corresponding Author: Guosheng Zou; E-mail: 13710870828@163.com

Abstract
Objectives
To investigate the in vivo tissue distribution and hepatic exposure mechanisms of ferulic acid, ligustrazine, and (Z)-ligustilide, the main active constituents of Chuanxiong Rhizome, and to elucidate the transport mechanisms involved in their hepatic uptake.
Method
Chuanxiong Rhizome was extracted using supercritical fluid extraction, and the concentrations of ferulic acid, ligustrazine, and (Z)-ligustilide were quantified by high-performance liquid chromatography and identified by secondary mass spectrometry. Male rats were administered the extract intragastrically at a dose of 1.5 g/kg. Blood, liver, spleen, lungs, and kidneys were collected at designated time points post-administration to determine tissue concentrations of the compounds. Hepatic uptake studies were performed using isolated normal rat hepatocytes obtained via the two-step collagenase perfusion method. The effects of temperature, metabolic inhibitors, and specific transporter inhibitors on hepatic uptake were evaluated to clarify transport mechanisms.
Results
All three compounds were rapidly distributed after oral administration, with significantly higher exposure observed in the liver compared with other tissues. Hepatocyte uptake was temperature-dependent and markedly reduced by metabolic and transporter inhibitors, indicating an active transport process. Ferulic acid uptake was primarily mediated by organic anion transporters, while ligustrazine uptake involved organic cation transporters. (Z)-Ligustilide showed notable hepatic accumulation, suggesting transporter-associated uptake, although its specific transport mechanism was less clearly defined.
Conclusion
Ferulic acid, ligustrazine, and (Z)-ligustilide from Chuanxiong Rhizome exhibit pronounced liver exposure following oral administration. This preferential hepatic distribution is largely attributed to active transport mechanisms, with organic anion and cation transporters playing key roles in the hepatic uptake of ferulic acid and ligustrazine, respectively. These findings provide mechanistic insight into the liver-targeting characteristics and pharmacological actions of Chuanxiong Rhizome.
Keywords: Chuanxiong Rhizome, Ferulic acid, ligustrazine, (Z)-ligustilide, hepatic exposure.