Highly potent, but poorly water-soluble, drug candidates are common outcomes of contemporary drug discovery programmes and present a number of challenges to drug development - most notably, the issue of reduced systemic exposure after oral administration. However, it is increasingly apparent that formulations containing natural and/or synthetic lipids present a viable means for enhancing the oral bioavailability of some poorly water-soluble, highly lipophilic drugs. This Review details the mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic drugs and provides a perspective on the possible future applications of lipid-based delivery systems. Particular emphasis has been placed on the capacity of lipids to enhance drug solubilization in the intestinal milieu, recruit intestinal lymphatic drug transport (and thereby reduce first-pass drug metabolism) and alter enterocyte-based drug transport and disposition.

Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs

Lipid-based delivery systems and intestinal lymphatic drug transport : A mechanistic update

Intestinal lymphatic transport for drug delivery

The role of specific phospholipids (PLs) in lipid transport has been difficult to assess due to an inability to selectively manipulate membrane composition in vivo. Here we show that the phospholipid remodeling enzyme lysophosphatidylcholine acyltransferase 3 (Lpcat3) is a critical determinant of triglyceride (TG) secretion due to its unique ability to catalyze the incorporation of arachidonate into membranes. Mice lacking Lpcat3 in the intestine fail to thrive during weaning and exhibit enterocyte lipid accumulation and reduced plasma TGs. Mice lacking Lpcat3 in the liver show reduced plasma TGs, hepatosteatosis, and secrete lipid-poor very low-density lipoprotein (VLDL) lacking arachidonoyl PLs. Mechanistic studies indicate that Lpcat3 activity impacts membrane lipid mobility in living cells, suggesting a biophysical basis for the requirement of arachidonoyl PLs in lipidating lipoprotein particles. These data identify Lpcat3 as a key factor in lipoprotein production and illustrate how manipulation of membrane composition can be used as a regulatory mechanism to control metabolic pathways.

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Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion

The current state of knowledge concerning the absorption and transport of dietary fat with emphasis on long-chain polyunsaturated n−3 fatty acids in mammals is reviewed. It is apparent that long-chain polyunsaturated n−3 fatty acids, either as free acids or as part of triglycerides, are readily absorbed in the gut and transported by the circulatory system. Indeed, it would appear that long-chain polyunsaturated n−3 fatty acids are digested, absorbed and transported similarly to other long-chain fatty acids with only minor variations, although there is much that is still not understood about these processes. The main unresolved issues in the area of the absorption and transport of long-chain polyunsaturated n−3 fatty acids appear to be: 1) If they, when located in the 2-position of triglycerides, have unique metabolic pathways; and 2) whether the unnatural forms, i.e., methyl or ethyl ester derivatives, are suitable vehicles for administration as dietary supplements. The effect in man of dietary, long-chain polyunsaturated n−3 fatty acids on blood serum lipid and lipoprotein levels, particularly the low density lipoproteins, remains controversial, except for the well-documented reduction in serum triglyceride levels. Also, there is uncertainty regarding their distribution and metabolism in tissues. Finally, if the consumption of long-chain polyunsaturated n−3 fatty acids has beneficial health consequences, what is the appropriate therapeutic dose? In view of these important, unresolved issues and uncertainties, it would seem prudent to direct additional research toward a better understanding of the overall process by which fat is digested, absorbed and transported.

John A. Balint

Papers

Role of biliary lecithin in lymphatic transport of fat.