ABSTRACT
Liposomes have been used in pharmacology for more than two decades now. First, they have been used as a tool for the delivery of active pharmacological ingredients. Liposomes, by providing the enclosed aqueous compartment, protect encapsulated active compounds from metabolic degradation. When properly designed, they also improve the compound biodistribution and/or reduce side effects. Liposomes are also used in the new drug development process serving as an experimental model of biological membranes. Due to the extensive legal regulations and rigorous quality requirements, the current drug discovery and development processes are a complex effort requiring large resources and taking more than 10 years to complete.1-3 In order to reduce the amount of resources and time needed for the development of a new drug,
there are continuous efforts to introduce cost-and time-effective methodologies. In this chapter, the description of liposome application as a model of biological barriers is presented along with the description of experimental strategies and measurement techniques for the determination of parameters critical for a drug. 9.1 Introduction
For most pharmacological formulations, the first step in determining the drug’s fate within the body is its absorption. In order to be absorbed, the drug must be in a dissolved form; thus, the solubility is the first critical parameter. Other factors controlling the rate of drug absorption are the degree of ionization (pKa and the pH of the solution), lipophilicity (lipid-to-water partition coefficient log K and the apparent lipid-to-water partition coefficient log D), and chemical stability. Once a drug has been absorbed, it has to be distributed throughout the body. In some approaches, the fate of the compound in the body is presented in terms of fluxes between various compartments. An example of such approach is schematically presented, for an orally delivered drug, in Fig. 9.1. The drug flux is reduced at barriers between compartments, and this is what limits its availability at the targeted location. Therefore, the fate of an active compound can be dissected into a series of discrete events, which can be modeled and evaluated individually. This makes possible the identification of critical descriptors, which quantitate the capacity of a compound to cross a specific barrier. The nature of barriers can be different, ranging from the metabolic transformation to a physical obstacle, i.e., biological membranes.4 In order to assess the effect of a barrier on the quantity of the active compound available, simplified model experimental systems are needed. The recurring element of each barrier is the presence of proteins and membranes.
