Yeap Yan Yan, Trevaskis Natalie L, Porter Christopher J H
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria, 3052, Australia.
Mol Pharm. 2013 Jul 1;10(7):2601-15. doi: 10.1021/mp400035z. Epub 2013 Jun 10.
Co-administration of poorly water-soluble drugs (PWSD) with dietary or formulation lipids stimulates the formation of lipid colloidal phases such as vesicular and micellar species, and significantly expands the drug solubilization capacity of the small intestine. The mechanism of drug absorption from the solubilizing phases, however, has not been fully elucidated. Recently, we observed that drug supersaturation may be triggered during endogenous processing of lipid colloidal phases containing medium-chain lipid digestion products and that this may represent a mechanism to reverse the reduction in thermodynamic activity inherent in drug solubilization and thereby enhance absorption. The current studies expand these preliminary findings and explore the supersaturation tendency of five model PWSD during endogenous processing of intestinal colloidal phases containing long-chain lipid digestion products. Bile-lipid concentration ratios progressively increase during colloid transit through the gastrointestinal tract due to biliary dispersion of lipid digestion products and lipid absorption. The supersaturation potential was therefore evaluated under conditions of increasing bile and decreasing lipid concentrations and was found to be greater for the basic drugs cinnarizine (CIN) and halofantrine (HF), than the neutral drugs fenofibrate (FF) and danazol (DAN), and acidic drug meclofenamic acid (MFA). Assessment of intestinal absorptive flux using rat jejunal perfusion experiments subsequently showed that the absorption enhancement afforded by bile dilution of lipid colloidal phases was greater for CIN than DAN. The results confirm that bile plays a significantly greater role in the absorption of CIN (a weak base) from long-chain intestinal colloids when compared to DAN (an uncharged molecule) and that the difference reflects a greater propensity for supersaturation as intestinal colloids are dispersed and diluted by bile. The data suggest that coadministered digestible lipids may be particularly suited to enhance the absorption of poorly water-soluble weak bases.
将难溶性药物（PWSD）与膳食或制剂脂质共同给药会刺激脂质胶体相（如囊泡和胶束物种）的形成，并显著扩大小肠的药物增溶能力。然而，药物从增溶相中吸收的机制尚未完全阐明。最近，我们观察到在含有中链脂质消化产物的脂质胶体相的内源性加工过程中可能会引发药物过饱和，这可能代表一种机制，可逆转药物增溶中固有的热力学活性降低，从而增强吸收。当前的研究扩展了这些初步发现，并探索了五种模型PWSD在含有长链脂质消化产物的肠道胶体相的内源性加工过程中的过饱和趋势。由于脂质消化产物的胆汁分散和脂质吸收，在胶体通过胃肠道的过程中，胆汁 - 脂质浓度比会逐渐增加。因此，在胆汁浓度增加和脂质浓度降低的条件下评估了过饱和潜力，发现碱性药物桂利嗪（CIN）和卤泛群（HF）的过饱和潜力大于中性药物非诺贝特（FF）和达那唑（DAN），以及酸性药物甲氯芬那酸（MFA）。随后使用大鼠空肠灌注实验评估肠道吸收通量，结果表明，胆汁稀释脂质胶体相对CIN的吸收增强作用大于DAN。结果证实，与DAN（一种不带电荷的分子）相比，胆汁在从长链肠道胶体中吸收CIN（一种弱碱）方面发挥着显著更大的作用，并且这种差异反映出随着肠道胶体被胆汁分散和稀释，过饱和的倾向更大。数据表明，共同给药的可消化脂质可能特别适合增强难溶性弱碱的吸收。
