Guiding precision medicine strategy for intravenous ginsenosides via pharmacokinetic-informed bioinformatic approaches: a study on XueShuanTong

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-01 DOI:10.1016/j.phymed.2025.156716

Wei-Wei Jia , Nan-Nan Tian , Zi-Jing Song , Xiao-Fang Lan , Xi-He Yang , Fei-Fei Du , Feng-Qing Wang , Chen Cheng , Xiao-Yan Xia , Yi-Mei Zeng , Ying Rao , Jun-Ling Yang , Chuan Li

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引用次数: 0

Abstract

Background

Intravenous ginsenosides, derived from Panax species, are widely used in China. XueShuanTong injection, enriched with ginsenosides Rb₁ and Rg₁, is recommended for unstable angina treatment. Although effective, it may cause adverse effects, especially in patients with renal or hepatic impairment, as these organs are vital in ginsenosides’ systemic exposure.

Purpose

This investigation aimed to inform precision medicine by employing a physiologically based pharmacokinetic (PBPK) model to evaluate transporter-mediated interactions between both ginsenosides and their systemic exposure in patients with organ impairment, thereby ensuring safety.

Methods

Interactions between ginsenosides Rb₁ and Rg₁, mediated by human and rat transporters, were characterized at both cellular and vesicular levels. Their interactions with human organic anion-transporting polypeptide (OATP)1B3 and rat Oatp1b2 were evaluated when administered together or as part of XueShuanTong in both rats and humans. PBPK models incorporating OATP-mediated hepatobiliary excretion were developed to characterize their interactions and pharmacokinetics, providing guidance for precision medicine in these patients.

Results

Ginsenoside Rb₁ was demonstrated to inhibit human OATP1B3 (Oatp1b2 in rats)-mediated cellular uptake, significantly increasing exposure levels of ginsenoside Rg₁ in rats by impairing hepatobiliary elimination. Mechanistic models effectively replicated the pharmacokinetic profiles and the interactions of ginsenosides Rb₁ and Rg₁. These validated models revealed that decreases in GFR, hematocrit, hepatic volume, and/or OATP1B3 expression and activity in patients with renal or hepatic impairment significantly increased the systemic exposure levels of both ginsenosides. Moreover, the models provided valuable insights into the mechanism of “albumin-facilitated dissociation” associated with ginsenoside Rb₁, an OATP1B3 inhibitor. This understanding is crucial for predicting the risk of drug-drug interactions involving drugs with high plasma protein binding.

Conclusions

By incorporating these key patient-specific physiological parameters into the models, this investigation provides practical guidance for optimizing dosing strategies and improving the therapeutic efficacy of ginsenoside-containing injections, including XueShuanTong, in patients with complex conditions.

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基于药代动力学的生物信息学方法指导静脉注射人参皂苷的精准医学策略：血栓通的研究

人参皂苷是一种从人参属植物中分离出来的药物，在中国被广泛应用。血栓通注射液富含人参皂苷Rb1和Rg1，推荐用于不稳定型心绞痛的治疗。虽然有效，但可能会引起不良反应，特别是对肾脏或肝脏受损的患者，因为这些器官对人参皂苷的全身暴露至关重要。目的：本研究旨在通过采用基于生理的药代动力学（PBPK）模型来评估两种人参皂苷之间的转运蛋白介导的相互作用及其在器官损害患者中的全身暴露，从而为精准医学提供信息，从而确保安全性。方法人参皂苷Rb1和Rg1之间的相互作用，在细胞和水泡水平上由人和大鼠转运体介导。在大鼠和人体内，分别评价其与人体有机阴离子转运多肽（OATP）1B3和大鼠Oatp1b2的相互作用。建立了包含ooatp介导的肝胆排泄的PBPK模型，以表征它们的相互作用和药代动力学，为这些患者的精准医疗提供指导。结果人参皂苷Rb1可抑制人OATP1B3（大鼠Oatp1b2）介导的细胞摄取，通过损害肝胆清除显著增加人参皂苷Rg1在大鼠体内的暴露水平。机制模型有效地复制了人参皂苷Rb1和Rg1的药代动力学特征和相互作用。这些经过验证的模型显示，肾或肝功能损害患者GFR、红细胞压积、肝脏体积和/或OATP1B3表达和活性的降低显著增加了两种人参皂苷的全身暴露水平。此外，该模型还为“白蛋白促进解离”与人参皂苷Rb1 （OATP1B3抑制剂）相关的机制提供了有价值的见解。这种理解对于预测涉及高血浆蛋白结合药物的药物-药物相互作用的风险至关重要。结论通过将这些关键的患者特异性生理参数纳入模型，为优化含人参皂苷注射液的给药策略，提高包括血栓通在内的含人参皂苷注射液对复杂病情患者的治疗效果提供了实践指导。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.