Guiding precision medicine strategy for intravenous ginsenosides via pharmacokinetic-informed bioinformatic...

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.

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.

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.

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.

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.