Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia.
J Pharm Sci. 2013 Jul;102(7):2395-408. doi: 10.1002/jps.23597. Epub 2013 May 20.
This work investigates the influence of drug absorption route (intestinal lymphatics vs. blood supply) on drug pharmacokinetics and tissue distribution. To achieve this aim, the pharmacokinetics and tissue distribution of model compounds [1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane, DDT; halofantrine] and lipids were assessed following intravenous delivery in lymph lipoproteins or plasma, and were found to differ significantly. For DDT, the clearance (CL) and volume of distribution (Vd ) were higher, whereas for halofantrine, CL and V(d) were lower, after entry in lymph versus plasma due, in particular, to differences in adipose tissue and liver uptake. In a recent study, halofantrine CL and V(d) were similar following entry in lymph or entry in plasma into the systemic circulation of animals predosed with lymph, whereas in the current study, predosing lymph did not influence DDT CL and V(d). For compounds such as DDT, changes to the route of absorption may thus directly impact on pharmacokinetics and tissue distribution, whereas for halofantrine factors that influence lymphatic transport may, by altering systemic lipoprotein concentrations, indirectly impact pharmacokinetics and tissue distribution. Ultimately, careful control of dosing conditions (formulation, prandial state), and thus the extent of lymphatic transport, may be important in assuring reproducible efficacy and toxicity for lymphatically transported drugs.
本研究旨在探讨药物吸收途径（肠淋巴途径与血液供应）对药物药代动力学和组织分布的影响。为此，我们评估了模型化合物[1,1-双（4-氯苯基）-2,2,2-三氯乙烷（DDT）；卤泛群]和脂质经肠淋巴脂蛋白或血浆静脉给药后的药代动力学和组织分布情况，结果发现两者存在显著差异。DDT 经淋巴进入体内后，其清除率（CL）和分布容积（Vd）较高，而卤泛群则相反，这主要归因于脂肪组织和肝脏摄取的差异。在最近的一项研究中，在预先给予淋巴的动物中，卤泛群经淋巴或血浆进入体循环后的 CL 和 V(d)相似，但在本研究中，预先给予淋巴并未影响 DDT 的 CL 和 V(d)。因此，对于 DDT 等化合物，吸收途径的改变可能直接影响药代动力学和组织分布，而对于卤泛群，影响淋巴转运的因素可能通过改变系统脂蛋白浓度，间接影响药代动力学和组织分布。最终，仔细控制给药条件（制剂、进食状态），从而控制淋巴转运的程度，对于确保具有淋巴转运的药物具有可重现的疗效和毒性可能非常重要。
