Rationale and applications of lipids as prodrug carriers

Lipidic prodrugs, also called drug-lipid conjugates, have the drug covalently bound to a lipid moiety, such as a fatty acid, a diglyceride or a phosphoglyceride. Drug-lipid conjugates have been prepared in order to take advantage of the metabolic pathways of lipid biochemistry, allowing organs to be targeted or delivery problems to be overcome. Endogenous proteins taking up fatty acids from the blood stream can be targeted to deliver the drug to the heart or liver. For glycerides, the major advantage is the modification of the pharmacokinetic behavior of the drug. In this case, one or two fatty acids of a triglyceride are replaced by a carboxylic drug. Lipid conjugates exhibit some physico-chemical and absorption characteristics similar to those of natural lipids. Non-steroidal, anti-inflammatory drugs such as acetylsalicylic acid, indomethacin, naproxen and ibuprofen were linked covalently to glycerides to reduce their ulcerogenicity. Mimicking the absorption process of dietary fats, lipid conjugates have also been used to target the lymphatic route (e.g., L-Dopa, melphalan, chlorambucil and GABA). Based on their lipophilicity and resemblance to lipids in biological membranes, lipid conjugates of phenytoin were prepared to increase intestinal absorption, whereas glycerides or modified glycerides of L-Dopa, glycine, GABA, thiorphan and N-benzyloxycarbonylglycine were designed to promote brain penetration. In phospholipid conjugates, antiviral and antineoplasic nucleosides were attached to the phosphate moiety. After presenting the biochemical pathways of lipids, the review discusses the advantages and drawbacks of lipidic prodrugs, keeping in mind the potential pharmacological activity of the fatty acid itself.