LIPID-BASED FORMULATIONS FOR ORAL ADMINISTRATION: OPPORTUNITIES FOR BIOAVAILABILITY ENHANCEMENT AND LIPOPROTEIN TARGETING OF LIPOPHILIC DRUGS

The identification of increasingly complex intracellular drug targets, escalating requirements in terms of drug potency and the use of combinatorial chemistry libraries and in vitro receptor-based activity assays, has led to a trend toward the identification of increasingly lipophilic lead molecules. The clinical usefulness of highly lipophilic, poorly water-soluble drugs, however, is often limited by their low and variable oral bioavailability, and although co-administration with lipids, lipidic excipients, or fatty meals may improve the bioavailability of lipophilic drugs, the mechanistic aspects of this enhancement are incompletely understood. The inherent physicochemical properties of lipophilic drug molecules dictate that they become associated with endogenous lipidic microdomains, ranging from lipids and lipid digestion products within the gastrointestinal tract (GIT) to lymph and plasma lipoproteins in the systemic circulation. The affinity with which lipophilic drugs bind to, and interchange between, these carrier systems can have a significant impact on the free drug fraction available for absorption, distribution, metabolism, and excretion and can therefore play a major role in defining both drug pharmacokinetics and therapy. J. OF RECEPTOR & SIGNAL TRANSDUCTION RESEARCH, 21(2&3), 215–257 (2001)