Physicochemical Properties Of Drugs

An early review that considers the physical chemistry of molecules in relation to brain entry is that of Friedemann (1). While this author accepted a role for lipid solubility, his thesis is almost entirely devoted to the view that molecular charge is crucial for penetration of non-lipid-soluble compounds, cationic molecules being permeant and anionic nonpenetrating. However, it was Krogh (2), in his great survey of exchanges through the surface of living cells and across living membranes generally, who concluded that in the search for drugs that act on the CNS one should be guided by a substance's solubility in lipids rather than by its electrical charge. He indicated that the cerebral capillaries have the general properties of the cell membrane and that they may even have secretory properties (i.e., be capable of active transport). Over half a century ago, Krogh foresaw much of what we now know to be true of the cerebral endothelium.

Davson (3) related rate of exchange in cerebrospinal fluid (CSF) and brain to molecules in a series, including thiourea itself and a range of alkyl-substituted thioureas. The rate clearly varied with the degree of hydrocarbon insertion (i.e., also with the solubility in lipid solvents). Later, it became fashionable to compare rate of exchange in CSF or in CSF and brain with the measured partition coefficient of the compound between a fat solvent and water. Thus Rall et al. (4) matched rate of exchange of each of a series of sulfonamides with its respective nonionized fraction and to its chloroform-water partition coefficient. Mayer and colleagues (5) compared rates for a different series of drugs in CSF and brain with the respective partition coefficients in heptane, benzene, and chloroform against water. More recently it has become usual to relate the logarithm of brain permeation into brain with the logarithm of octanol-water partition coefficient log Poct (e.g., Rapoport and Levitan, 6). This change in use of lipid solvent as a standard of comparison seems to have been based on studies of the pharmacological activities of molecules on the brain rather than on measured penetrations (7). These very different measurements may or may not give comparable results. No rigorous studies of the value of different lipid solvents in predicting BBB permeation from partitioning seem to have been made. All lipid solvents mentioned seem to yield tolerable comparisons, but inspection of regressions plotted in the literature of large groups of compounds suggests that measured values of permeability may in some instances differ from predicted values by as much as an order of magnitude.


A more fundamental approach is to directly relate measured permeability of the blood-brain barrier or steady state distribution of a compound between blood and brain to molecular factors. Thus the linear free energy relationship permits distribution of dissolved molecules between phases to be related to the quantitative influence of certain solute molecular ''descriptors'' (8). These descriptors include excess molar refraction, dipolarity/polarizability, overall hydrogen bonding acidity and basicity, respectively, and the characteristic volume of McGowan. The method has been applied to both blood-brain distribution (9) and to permeability at the BBB (10). In both cases the method provided substantially better predictions of solute behavior than did the octanol-water partition coefficient. The approach is reviewed in much greater detail elsewhere in this volume (11).

The partial success of partition coefficients and the greater precision of the Abraham relation in predicting permeability of the BBB must depend on the dependence of rate of passive diffusion across the cerebral endothelium on the level of solute partitioning in the lipid plasma membranes of the endo-thelial cells. Hence, it is evident that where other specific processes are involved in enhancing or in restraining movement of molecules across the endo-thelium, this prediction on its own will underestimate or overestimate, respectively, the true permeability. The number of observed exceptions to molecular transport by passive diffusion alone are increasing and are detailed in several later chapters.


A number of nutrient molecules are transferred across the BBB by ''facilitated diffusion.'' The transported molecules cross the plasma membranes by interacting with intramembrane transporter proteins related to water-filled channels. The two systems with the highest capacity are that for d-glucose and certain other sugars (the gene product Glut 1) and that for large neutral amino acids, the so-called l-system. The first has been sequenced for a number of mammalian species, the preferred structure of the sugar substrate understood, and models for sugar translocation across the membrane discussed (12). The high maximum transport capacity at the blood-brain barrier, 4 |j,mol min^g-1 in the rat and 1 mol min^g-1 in man (13), suggests that this system might be used for transport into brain of a drug linked to a d-pyranose sugar of appropriate structure.

The l transporter at the blood-brain barrier has somewhat different Km values for its substrate amino acids than the Km values exhibited in other tissues; hence it is regarded as a separate isoform and has been designated L1 (14). The general l transporter has recently been sequenced (15) and the three-dimensional structure of the binding site for neutral amino acids at the blood-brain barrier has been largely established by computer modeling (16). Marked preference for phenylalanine analogues was exhibited when a neutral substituent was at the meta position. The anticancer drugs melphalan and d,l-2-NAM-7 are appreciably transported by the L1 process. The latter drug has an exceptionally high affinity for the transporter, with a Km of about 0.2 |J,M (17). The transporter also has pharmaceutical significance in that it carries l-Dopa, used in the therapy of Parkinson's disease.

The transporter for basic amino acids is also of interest in that the gene has been cloned for the murine (18), rat, and human system. The Vmax is rather less than that for the L1 transporter, at 24 nmol min(14). With the advent of therapies directed toward DNA, a further system of transporters of relevance is that with affinity for certain nucleosides analogues. The components are being characterized in various tissues (19), but that at the blood-brain barrier (20) deserves further research.

It is becoming increasingly apparent that active transport plays an important role in restricting the entry of certain drugs into brain. The function of active transport in pumping certain organic anions, such as p-aminohippurate, from CSF to blood has been recognized since the early 1960s (21). The choroid epithelium is particularly effective in this activity, but it also occurs at the cerebral endothelium (22). The system is now called the multispecific organic anion transporter (23) and is effective in removing penicillin and azidothymi-dine (AZT) from CSF and brain (24). The efflux is blocked by probenecid.

It had been supposed that there might be a molecular weight limit on drug entry into brain from blood, uptake of drugs above about 800 kDa being small (25). However, drugs Levin studied, such as doxorubicin, vincristine, and etopside, are now known to be substrates for a potent mechanism that restricts brain entry of a wide range of drugs. Thus P-glycoprotein is sited in the apical (blood-facing) plasma membrane of the endothelium and is able to utilize ATP in pumping certain drugs from endothelial cells into blood, thus reducing brain entry, as reviewed by Borst and Schinkel (26) and in this volume by Begley et al. (23) and by Mayer (27). Substrates include vinblastine, ivermectin, digoxin, and cyclosporine. Molecules transported are often lipo-

philic and larger in size than many drugs. The structures of transported molecules differ markedly, and the structural characteristics of the binding site have not yet been fully defined.

Movement into or through the cerebral endothelium of molecules of the size of peptides and proteins (e.g., insulin, transferrin, lipoproteins) may depend on receptor-mediated endocytosis. Alternatively, cationization of albumin may stimulate a nonspecific endocytosis. Significant flux into brain of drugs linked to monoclonal antibodies against the transferrin receptor or the insulin receptor also takes place. This topic is also reviewed in this volume (28).

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