Effect of a high-fat meal on absorption and disposition of lipophilic compounds: The importance of degree of association with triglyceride-rich lipoproteins
Effect of a high-fat meal on absorption and disposition of lipophilic compounds: The importance of degree of association with triglyceride-rich lipoproteins
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DOI：
10.1016/j.ejps.2007.05.109
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发表时间：
2007-09-01
影响因子：
4.6
通讯作者：
Hoffman, Amnon
中科院分区：
文献类型：
--
作者：
Gershkovich, Pavel;Hoffman, Amnon
高脂餐后，富含甘油三酯的脂蛋白（TRL）在肠道中组装，并通过淋巴吸收进入血液循环，产生暂时性高脂血症。本研究的目的是验证以下假设：这种一过性急性餐后高脂血症通过相同的潜在机制影响亲脂性药物在吸收和处置水平上的药代动力学，即活性亲脂性化合物与血浆（处置）或肠上皮细胞（淋巴转运）中的TRL相关。使用两种模型化合物，DDT与乳糜微粒和地西泮的高亲和力，不结合乳糜微粒，在大鼠中评估这一概念。与水处理组相比，口服花生油显著增加了静脉推注给药后血浆DDT浓度的AUC。另一方面，在油和水处理的大鼠中，IV推注给药后地西泮的AUC相同。虽然滴滴涕是已知的具有显着的淋巴生物利用度，地西泮具有可忽略不计的肠道淋巴转运（0.014 - 0.004%的给定剂量）。总之，广泛结合TRL的亲脂性分子在高脂餐后易于肠道淋巴转运和吸收后处置变化（清除率和分布容积降低）。(c)2007 Elsevier B. V.保留所有权利。
Following a high-fat meal, triglyceride-rich lipoproteins (TRL) are assembled in the gut and absorbed via the lymph into the blood circulation, producing a temporal hyperlipidemia. The purpose of this study is to verify the hypothesis that this transient acute postprandial hyperlipidemia affects the pharmacokinetics of lipophilic drugs on both absorption and disposition levels by the same underlying mechanism, namely the association of active lipophilic compounds with TRL in the plasma (disposition) or within the enterocyte (lymphatic transport). This concept was assessed in rats using two model compounds, DDT with high affinity to chylomicrons and diazepam which does not bind to chylomicrons. Oral administration of peanut oil significantly increased the AUC of plasma DDT concentrations following its IV bolus administration in comparison to a water treated group. On the other hand, the AUC of diazepam following IV bolus administration was the same in oil and water treated rats. While DDT is known to have significant lymphatic bioavailability, diazepam has negligible intestinal lymphatic transport (0.014 0.004% of a given dose). In conclusion, lipophilic molecules that bind extensively to TRL will be prone to both intestinal lymphatic transport and to post-absorptive changes in disposition (decrease in clearance and volume of distribution) following a high-fat meal. (c) 2007 Elsevier B.V. All rights reserved.