Gershkovich Pavel, Shtainer Daniel, Hoffman Amnon
Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
Int J Pharm. 2007 Mar 21;333(1-2):1-4. doi: 10.1016/j.ijpharm.2007.01.012. Epub 2007 Jan 19.
A high-fat meal induces transient hyperlipidemia characterized by elevated triglyceride-rich lipoproteins (TRL) which are composed mainly of chylomicrons. The purpose of this work was to investigate the effect of this transient hyperlipidemia on the pharmacodynamics of lipophilic drugs, using DDT as a model compound since it binds extensively to TRL and has a distinct neurotoxic effect. The postprandial hyperlipidemia in rats was induced by oral administration of peanut oil and was monitored by measurement of plasma triglyceride levels. The control group received water instead of oil. The rats received a continuous intravenous infusion of DDT (10 mg/h) until onset of a predefined pharmacodynamic endpoint (facial muscle tremor). Plasma and brain samples were then obtained and assayed for DDT. Rats with postprandial hyperlipidemia required higher dose of DDT to induce onset of facial muscle tremor. At the pharmacodynamic endpoint, oil treated rats had significantly higher concentrations of DDT in plasma and in the chylomicron fraction, but DDT brain concentrations were the same in both groups. In conclusion, a high-fat meal induces postprandial hyperlipidemia that may significantly alter the pharmacological profile of lipophilic compounds that bind to TRL. This is due to alteration of the distribution characteristics of the lipophilic compound through its association with postprandial lipoproteins. However, this pharmacokinetic phenomenon did not affect the concentration-effect relationship at the site of action in the brain.
高脂餐会引发短暂性高脂血症，其特征是富含甘油三酯的脂蛋白（TRL）升高，而TRL主要由乳糜微粒组成。本研究的目的是，以滴滴涕作为模型化合物来研究这种短暂性高脂血症对亲脂性药物药效学的影响，因为滴滴涕与TRL广泛结合且具有明显的神经毒性作用。通过口服花生油诱导大鼠餐后高脂血症，并通过测量血浆甘油三酯水平进行监测。对照组给予水而非油。大鼠持续静脉输注滴滴涕（10毫克/小时），直至出现预定义的药效学终点（面部肌肉震颤）。然后采集血浆和脑样本并检测滴滴涕含量。餐后高脂血症大鼠需要更高剂量的滴滴涕才能诱发面部肌肉震颤。在药效学终点时，经油处理的大鼠血浆和乳糜微粒部分中的滴滴涕浓度显著更高，但两组大鼠脑中的滴滴涕浓度相同。总之，高脂餐会引发餐后高脂血症，这可能会显著改变与TRL结合的亲脂性化合物的药理学特征。这是由于亲脂性化合物与餐后脂蛋白结合后，其分布特征发生了改变。然而，这种药代动力学现象并未影响脑中作用部位的浓度-效应关系。
