Ramisetty Bhargavi Srija, Singh Rashim, Hu Ming, Wang Michael Zhuo
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66047, USA.
Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204, USA.
Pharmaceutics. 2025 Jun 23;17(7):814. doi: 10.3390/pharmaceutics17070814.
: Glucuronide recycling in the gut and liver profoundly affects the systemic and/or local exposure of drugs and their glucuronide metabolites, impacting both clinical efficacy and toxicity. This recycling also alters drug exposure in the colon, making it critical to establish local concentration for drugs targeting colon (e.g., drugs for colon cancer and inflammatory bowel disease). : In this study, a parent-metabolite middle-out physiologically based pharmacokinetic (PBPK) model was built for genistein and its glucuronide metabolite to estimate the systemic and local exposure of the glucuronide and its corresponding aglycone in rats by incorporating UDP-glucuronosyltransferase (UGT)-mediated metabolism and transporter-dependent glucuronide disposition in the liver and intestine, as well as gut microbial-mediated deglucuronidation that enables the recycling of the parent compound. : This parent-metabolite middle-out rat PBPK model utilized in vitro-to-in vivo extrapolated (IVIVE) metabolic and transporter clearance values based on in vitro kinetic parameters from surrogate species, the rat tissue abundance of relevant proteins, and saturable Michaelis-Menten mechanisms. Inter-system extrapolation factors (ISEFs) were used to account for transporter protein abundance differences between in vitro systems and tissues and between rats and surrogate species. Model performance was evaluated at multiple dose levels for genistein and its glucuronide. Model sensitivity analyses demonstrated the impact of key parameters on the plasma concentrations and local exposure of genistein and its glucuronide. Our model was applied to simulate the quantitative impact of glucuronide recycling on the pharmacokinetic profiles in both plasma and colonocytes. : Our study underlines the importance of glucuronide recycling in determining local drug concentrations in the intestine and provides a preliminary modeling tool to assess the influence of transporter-mediated drug-drug interactions on glucuronide recycling and local drug exposure, which are often misrepresented by systemic plasma concentrations.
肠道和肝脏中的葡萄糖醛酸苷循环深刻影响药物及其葡萄糖醛酸苷代谢物的全身和/或局部暴露，对临床疗效和毒性均有影响。这种循环还会改变结肠中的药物暴露，因此确定靶向结肠的药物（如用于结肠癌和炎症性肠病的药物）的局部浓度至关重要。
在本研究中，构建了一种母-代谢物中间向外的基于生理的药代动力学（PBPK）模型，用于研究染料木黄酮及其葡萄糖醛酸苷代谢物，通过纳入肝脏和肠道中尿苷二磷酸葡萄糖醛酸基转移酶（UGT）介导的代谢、转运蛋白依赖性葡萄糖醛酸苷处置以及肠道微生物介导的去葡萄糖醛酸化作用（可实现母体化合物的循环），来估计大鼠体内葡萄糖醛酸苷及其相应苷元的全身和局部暴露。
这种母-代谢物中间向外的大鼠PBPK模型利用了基于替代物种体外动力学参数、大鼠组织中相关蛋白丰度以及饱和米氏机制的体外到体内外推（IVIVE）代谢和转运蛋白清除值。系统间外推因子（ISEF）用于解释体外系统与组织之间以及大鼠与替代物种之间转运蛋白丰度的差异。在多个剂量水平下对染料木黄酮及其葡萄糖醛酸苷的模型性能进行了评估。模型敏感性分析表明关键参数对染料木黄酮及其葡萄糖醛酸苷血浆浓度和局部暴露的影响。我们的模型被应用于模拟葡萄糖醛酸苷循环对血浆和结肠细胞中药代动力学特征的定量影响。
我们的研究强调了葡萄糖醛酸苷循环在确定肠道局部药物浓度方面的重要性，并提供了一个初步的建模工具，以评估转运蛋白介导的药物-药物相互作用对葡萄糖醛酸苷循环和局部药物暴露的影响，而全身血浆浓度常常无法准确反映这些影响。
