Risk assessment of CYP3A induction by ginsenoside's metabolites from oral Panax notoginseng (sanqi) extract

In China, the integration of Chinese traditional medicine with Western medicine for the treatment of multifactorial diseases provides notable therapeutic benefits. Given this integration involving co-administration of herbal medicines and synthetic drugs, it is critical to evaluate the potential for associated drug interactions.

This investigation aimed to evaluate an oral extract of Panax notoginseng roots (Sanqi) for its potential to induce CYP3A activity, which may contribute to herb-drug interactions.

Human microbiota-associated (HMA) rats were used to determine whether repeated oral administration of Sanqi extract induces CYP3A activity. Cryopreserved primary rat and human hepatocytes were used to evaluate the ability of ginsenoside metabolites and their combinations to induce rat Cyp3a and human CYP3A. Fecal samples from HMA rats repeatedly treated with oral Sanqi extract were analyzed for microbial deglycosylation activity on ppt-type ginsenosides. Quantitative real-time polymerase chain reaction was used to measure mRNA levels of rat Cyp3a1 and Cyp3a2, and human CYP3A4 and CYP3A5. Liquid chromatography/mass spectrometry was used to quantify ginsenosides and their metabolites in rat samples and in vitro study samples. 16S rRNA gene sequencing was used to analyze intestinal microbiota composition.

Repeated oral administration of Sanqi extract did not induce hepatic Cyp3a expression in rats. Neither ginsenoside metabolites nor their combinations induced rat Cyp3a or human CYP3A in vitro. Systemic exposure to oxidized metabolites of 20(S)-protopanaxtriol showed significant accumulation in HMA rats following repeated administration of Sanqi extract. This accumulation pattern mirrored previous findings in humans. The increased systemic exposure to the oxidized metabolites was likely due to enhanced microbial deglycosylation activity resulting from repeated oral administration of the extract.

Oral Sanqi extract exhibits a low propensity to induce CYP3A. This limited potential for drug interactions supports its safe use in cardiovascular therapies, particularly in polypharmacy settings.