Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas 77030, USA.
J Pharm Sci. 2012 Mar;101(3):1281-301. doi: 10.1002/jps.22827. Epub 2011 Nov 22.
Drug elimination via glucuronidation pathway is a complex process involving glucuronide excretion. Glucuronide excreted into the gut lumen either directly from the enterocytes or from the hepatobiliary route can be recovered back to the precursor (aglycone) through bacteria-mediated hydrolysis. As a result, the pharmacokinetics [e.g., plasma terminal half-life (T(1/2))] of aglycone might be altered. Here, impact of intestinal glucuronide hydrolysis on the pharmacokinetics of aglycone is evaluated using physiologically based pharmacokinetic (PBPK) models with liver and/or intestine as eliminating organs. It is found that compared with its absence, the presence of intestinal glucuronide hydrolysis leads to increases in the oral systemic bioavailability (F(sys)) of aglycone. The magnitude of fold increase is positively correlated with the level of metabolism, as metabolic clearance mainly contributes to recycled amount of glucuronide. Although F(sys) is independent of the glucuronide efflux in a traditional model and a segregated-flow model of the intestine, dependence of F(sys) on the glucuronide efflux can be observed in a segmental segregated-flow model of the intestine and whole-body PBPK models. Interestingly, when the ratio of apical versus basolateral efflux intrinsic clearances (of glucuronide) is fixed, their effects on the intestinal bioavailability and F(sys) cease to exist. In addition, glucuronide hydrolysis can lead to a significantly delayed elimination of the aglycone as evidenced by a prolonged (e.g., a 2.1-fold increase) T(1/2). Surprisingly, when a pharmacokinetic profile for aglycone is simulated with a flat terminal portion (a reflection of the experimental observations), changes in the aglycone bioavailabilities are limited (i.e., ≤ 1.3-fold). In conclusion, this study explores the possible role of intestinal glucuronide hydrolysis in the disposition of aglycone via simulations utilizing various PBPK models. The mechanistic observations should be helpful to better understand the complex glucuronidation in vivo.
经葡萄糖醛酸化途径消除药物是一个复杂的过程，涉及葡萄糖醛酸苷的排泄。从肠细胞或肝胆途径直接排泄到肠腔中的葡萄糖醛酸苷，可通过细菌介导的水解作用恢复为前体（苷元）。因此，苷元的药代动力学[例如，血浆末端半衰期（T(1/2)）]可能会发生改变。在这里，使用具有肝脏和/或肠道作为消除器官的基于生理学的药代动力学（PBPK）模型来评估肠道葡萄糖醛酸苷水解对苷元药代动力学的影响。结果发现，与不存在相比，存在肠道葡萄糖醛酸苷水解会导致苷元的口服全身生物利用度（F(sys)）增加。增加的幅度与代谢水平呈正相关，因为代谢清除主要导致葡萄糖醛酸苷的再循环量增加。尽管 F(sys)在传统模型和肠道的分隔流模型中与葡萄糖醛酸苷的外排无关，但在肠道的分段分隔流模型和全身 PBPK 模型中可以观察到 F(sys)对葡萄糖醛酸苷外排的依赖性。有趣的是，当顶端与基底外侧外排内在清除率（葡萄糖醛酸苷）的比值固定时，它们对肠道生物利用度和 F(sys)的影响就不存在了。此外，葡萄糖醛酸苷水解可导致苷元的消除明显延迟，表现为半衰期延长（例如，增加 2.1 倍）。令人惊讶的是，当使用具有平坦末端部分（反映实验观察结果）模拟苷元的药代动力学曲线时，苷元生物利用度的变化是有限的（即，≤1.3 倍）。总之，本研究通过利用各种 PBPK 模型进行模拟，探讨了肠道葡萄糖醛酸苷水解在苷元处置中的可能作用。这些机制观察结果应该有助于更好地理解体内复杂的葡萄糖醛酸化过程。
