Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada. Faculty of Pharmacy & Pharmaceutical Sciences, 2142J Katz. Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, Alberta, Canada.
J Pharm Pharm Sci. 2018;21(1s):254s-270s. doi: 10.18433/jpps30217.
Most orally administered drugs gain access to the systemic circulation by direct passage from the enterocyte layer of the intestinal tract to the mesenteric blood capillaries. Intestinal lymphatic absorption is another pathway that certain drugs may follow to gain access to the systemic circulation after oral administration. Once absorbed, drug diffuses into the intestinal enterocyte and while in transit may associate with fats as they are processed into chylomicrons within the cells. The chylomicron-associated drug is then secreted from the enterocyte into the lymphatic circulation, thus avoiding the hepatic first-pass liver metabolism, and ultimately entering to the systemic circulation for disposition and action. Due to the possibility of parallel and potentially alternative absorptive pathways, mesenteric blood capillary and lymphatic drug exposure are both potential pathways of systemic availability for any individual drug. In this report, an in silico modeling approach was adopted to delineate the salient pharmacokinetic features of lymphatic absorption, and provide further guidance for the rationale design of drugs and drug delivery systems for lymphatic drug transport. The importance of hepatic extraction ratio, absorption lag time, lipoprotein binding, and the influence of competing portal and lymphatic pathways for systemic drug availability were explored using simulations. The degree of hepatic extraction was found to be an essential consideration when examining the influence of lymphatic uptake to overall oral drug bioavailability. Lymphatic absorption could potentially contribute to multiple peaking phenomena and flip flop pharmacokinetics of orally administered drugs.
大多数口服药物通过直接从肠道肠细胞层进入肠系膜毛细血管，从而进入体循环。肠道淋巴吸收是某些药物经口服后进入体循环的另一种途径。药物一旦被吸收，就会扩散到肠细胞内，在运输过程中可能会与脂肪结合，因为它们在细胞内被加工成乳糜微粒。与脂肪结合的药物随后从肠细胞分泌到淋巴循环中，从而避免了肝脏的首过代谢，最终进入体循环进行处置和作用。由于存在平行的、可能是替代的吸收途径，肠系膜毛细血管和淋巴药物暴露都是任何特定药物全身可用性的潜在途径。在本报告中，采用了一种计算建模方法来描述淋巴吸收的显著药代动力学特征，并为淋巴药物转运的药物和药物输送系统的合理设计提供进一步的指导。通过模拟，探讨了肝提取率、吸收滞后时间、脂蛋白结合以及门静脉和淋巴竞争途径对系统药物可用性的影响。在研究淋巴摄取对整体口服药物生物利用度的影响时，发现肝提取程度是一个重要的考虑因素。淋巴吸收可能有助于口服药物的多种峰现象和翻转药代动力学。
