Biological Aspects

The relation between lipid solubility and biological effects of drugs was recognized almost a century ago by Meyer [3] and by Overton [4], Some decades later, Pauling discovered a relationship between lipophilicity and anesthetic potency in a series of chem ically heterogeneous compounds [5], It soon became evident that a quantification, or even a description of lipophilicity in thermodynamic terms, is not practicable. Until now, only empirical scales of lipophilicity have been of importance in practice, some expressing the changes in free energy associated with solute transfer between two phases, others being dimensionless indices relating partitioning data of given solutes to a general standard. This latter approach is based on the assumption of linear free-energy changes and is represented by the Leffler-Grunwald operators [6]. It was, in fact, first employed by Hammett in 1935 to describe electronic properties of substituent groups attached to a fixed molecular backbone [7]. Later, Zahradnik and coworkers used responses obtained in two related biological systems to derive what is in fact, but not by name, a set of lipophilicity constants [8, 9]. Such attempts were not unique during the late 1950s and early 1960s. However, it is to the great credit of Hansch, Fujita and Leo that empirical constants can be readily used in pharmacology and toxicology [10, 11]. Besides deriving an extensive set of lipophilicity descriptors, the so-called Jt-values, Hansch and colleagues proved their apparent additive nature, thus establishing them as genuine substituent constants.

The structure and function of any biological system are closely related to the lipophilic properties of its component molecules. First, lipid-lipid interactions strongly influence the structure of biological membranes, and thereby the compartmentation of compounds within cell organelles. Second, transport and distribution processes within biological systems are to a large extent controlled by the lipophilicity of the system components. The highly hydrophobic interior of a bilayer membrane enables or facilitates the passage of lipophilic substances and prevents the free diffusion of polar molecules except water in and out of cells and organelles. By controlling both transport and compartmentation processes with some degree of selectivity, lipophilicity imposes an adjustable resistance to free diffusion, thus becoming the major obstacle to a random distribution of substances in biological systems, which would be entirely incompatible with life. The same is true for distribution within an organism where several physiological barriers control the access of endogenous and exogenous compounds to various organs and tissues. It is well established that the hemato-encephalic (blood-brain), placental and hemato-mammary (blood-mammary gland) barriers are of a very selective nature, so that specific transporter systems have to mediate the passage of vital compounds, the hydrophilicity of which prevents their passive membrane permeation.

Last, but not least, lipophilicity plays a dominating role in ligand-receptor interactions, e.g., in the binding of hormones, neurotransmitters, modifiers of cellular processes (e.g., growth, initiation, or repression factors) and drugs to their receptors. The same applies for enzyme-substrate, enzyme-inhibitor, antigen-antibody and other ligand-macromolecule interactions.

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