Arian Christopher M, O'Mahony Eimear T, Manwill Preston K, Graf Tyler N, Oberlies Nicholas H, Cech Nadja B, Clarke John D, Smith Jason G, Paine Mary F, Kelly Edward J, Thummel Kenneth E
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington.
Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina.
J Pharmacol Exp Ther. 2025 Jun;392(6):103597. doi: 10.1016/j.jpet.2025.103597. Epub 2025 May 3.
Continued growth in global sales of natural products has led to an increased risk of natural product-drug interactions that can compromise drug efficacy and safety. One such natural product, goldenseal, was shown to decrease systemic exposure to a subtherapeutic dose of oral metformin in healthy adults. A follow-up study involving therapeutic metformin doses and adults with type II diabetes demonstrated a metformin dose-dependent pharmacokinetic interaction with goldenseal. These results, along with no change in metformin half-life or renal clearance in both studies, suggested that the goldenseal-metformin interaction occurred in the gut via inhibition of an unidentified saturable intestinal transport process. We used enteroid monolayers derived from the duodenum of 4 healthy human adult donors to recapitulate the goldenseal-metformin interaction in vitro and identify the transporters involved in the observed in vivo interaction. Our results implicate thiamine transporter (ThTr) 2 as the predominant transporter involved in metformin uptake through the apical membrane, accounting for approximately 45% of total metformin intracellular accumulation. Additionally, goldenseal inhibited ThTr-2, but only under subsaturating metformin dosing concentrations. The goldenseal-metformin interaction mediated under therapeutic metformin dose conditions involves a low-affinity basolateral transporter, ThTr-1, which accounts for approximately 50% of inhibitable metformin apical to basolateral flux. However, a substantial fraction of metformin flux appears to involve paracellular transport. These results further elucidate the mechanism underlying the goldenseal-metformin interaction and suggest that enteroid monolayers are a promising model to study intestinal natural product-drug interactions. SIGNIFICANCE STATEMENT: The research presented in this article demonstrates the utility of enteroid monolayers to predict and ascertain the mechanisms of drug-drug and natural product-drug interactions. Using this model, the study was able to identify the transporters (thiamine transporter-1 and thiamine transporter-2) involved in metformin absorption that are inhibited by the natural product, goldenseal, which were previously unidentified.
天然产品全球销售额的持续增长导致了天然产品与药物相互作用的风险增加，这可能会影响药物疗效和安全性。其中一种天然产品白毛茛，已被证明会降低健康成年人口服亚治疗剂量二甲双胍的全身暴露量。一项后续研究涉及治疗剂量的二甲双胍和II型糖尿病成年人，结果表明二甲双胍与白毛茛之间存在剂量依赖性药代动力学相互作用。这些结果，以及两项研究中二甲双胍半衰期和肾清除率均无变化，表明白毛茛与二甲双胍的相互作用发生在肠道，是通过抑制一种未明确的可饱和肠道转运过程。我们使用来自4名健康成年供体十二指肠的类器官单层来在体外重现白毛茛与二甲双胍的相互作用，并确定参与观察到的体内相互作用的转运体。我们的结果表明硫胺转运体（ThTr）2是参与二甲双胍通过顶端膜摄取的主要转运体，约占二甲双胍细胞内总积累量的45%。此外，白毛茛抑制ThTr-2，但仅在亚饱和二甲双胍给药浓度下。在治疗性二甲双胍剂量条件下介导的白毛茛与二甲双胍的相互作用涉及一种低亲和力的基底外侧转运体ThTr-1，它约占可抑制的二甲双胍从顶端到基底外侧通量的50%。然而，相当一部分二甲双胍通量似乎涉及细胞旁转运。这些结果进一步阐明了白毛茛与二甲双胍相互作用的潜在机制，并表明类器官单层是研究肠道天然产品与药物相互作用的一个有前景的模型。意义声明：本文提出的研究证明了类器官单层在预测和确定药物-药物以及天然产品-药物相互作用机制方面的实用性。使用该模型，该研究能够识别参与二甲双胍吸收且被天然产品白毛茛抑制的转运体（硫胺转运体-1和硫胺转运体-2），这些转运体此前未被识别。
