Rationale and applications of lipids as prodrug carriers

Lipidic prodrugs, also called drug-lipid conjugates, have the drug covalent ly bound to a lipid moiety, such as a fatty acid, a diglyceride or a phosph oglyceride. Drug-lipid conjugates have been prepared in order to take advan tage of the metabolic pathways of lipid biochemistry, allowing organs to be targeted or delivery problems to be overcome. Endogenous proteins taking u p 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 fatt y acids of a triglyceride are replaced by a carboxylic drug. Lipid conjugat es exhibit some physico-chemical and absorption characteristics similar to those of natural lipids. Non-steroidal, antiinflammatory drugs such as acet ylsalicylic acid, indomethacin, naproxen and ibuprofen were linked covalent ly to glycerides to reduce their ulcerogenicity. Mimicking the absorption p rocess 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, lipi d conjugates of phenytoin were prepared to increase intestinal absorption, whereas glycerides or modified glycerides of L-Dopa, glycine, GABA, thiorph an and N-benzyloxycarbonylglycine were designed to promote brain penetratio n. In phospholipid conjugates, antiviral and antineoplasic nucleosides were attached to the phosphate moiety. After presenting the biochemical pathway s of lipids, the review discusses the advantages and drawbacks of lipidic p rodrugs, keeping in mind the potential pharmacological activity of the fatt y acid itself. (C) 2000 Elsevier Science B.V. All rights reserved.