around and completely encloses the fluid to form a vesicle. The vesicle is pinched off, passing some fluid and solutes across the membrane into the interior of the cell. Some solutes may bind a membrane receptor which triggers the endocytotic process.
Receptor-mediated endocytosis is an important transport mechanism for targeting drugs to certain cells. That strategy has been used successfully by designing drugs to mimic an endogenous protein, transported by receptor-mediated endocytosis. The protein analog can be synthesized using new techniques of biotechnology so that it binds to specific membrane receptors and therefore gains access by endocytosis only to those cells that have the receptor.
FILTRATION
Filtration is the process in which the solids and liquid of a system are separated by means of a porous membrane that allows passage of fluid, solutes and some particulate materials, while retaining particles too large to pass through the pores. It is a purely physical process in which the driving force for movement is a pressure gradient, the rate of filtration being dependent on this gradient and on the size of the particle to be filtered in relation to the size of the pore. Thus filtration is markedly different from the transfer processes already described.
We know that intact proteins can pass through various biologic barriers such as the capillary wall, and at the capillary level at least, their rate of movement is strongly dependent upon a pressure gradient. So when we consider filtration in terms of a biologic barrier, the process generally does not occur across cell membranes but through spaces between cells. Filtration can be important for the movement of large macromolecules and is an especially important process in the formation of urine and the ultimate elimination of substances from the body.
SYNOPSIS
Drugs or chemicals foreign to the body move across biologic barriers using the preexisting processes that serve to transport substances required for the maintenance and growth of living organisms. This movement of solutes across complex barriers is determined by the general principles governing transport across the membranes of cells which constitute the barrier. The membranes of all cells have functional similarity derived from their similar structural organization and chemical composition. The cell membrane is a structure containing a bimolecular layer of lipids with the hydrophobic
groups of the lipid oriented toward each other and the hydrophilic groups aligned at both surfaces. This lipid bilayer forms the matrix of a mosaic in which proteins are embedded;
the highly polar and ionic groups of the proteins protrude into the aqueous phase, and the nonpolar residues are largely buried in the interior of the membrane. These membrane proteins perform many important functions, including (1) contributing to the strength of the membrane; (2) acting as enzymes (cf. p. 154) to catalyze chemical reactions; (3) acting as carriers for transport of substances through the membrane; (4) providing discontinuities in the lipid bilayer which then serve as ‘pores’ for
passage of water-soluble materials through the membrane, and (5) acting as receptors.
The mechanism underlying biotransport can best be defined in terms of the forces responsible for movement of the solute and of the requirements of the process for cellular energy, Basic to all the mechanisms is the cellular energy needed to maintam the integrity and organization of the cell and its membrane, Passive, or simple, diffusion requires no additional expenditure of cellular energy, and movement occurs in the direction of the concentration gradient and in proportion to the physical force provided by the gradient.
The rate of passive diffusion is also determined by the lipid solubility, the degree of ionization and the molecular size of the solute. Facilitated diffusion, like passive diffusion, requires no further expenditure of cellular energy, and movement occurs only with the concentration gradient It differs from passive diffusion in that the physicochemical properties of the constituents of the membrane and those of the solute are insufficient to account for the rate of movement of the solutes. Therefore, the concept of temporary combination of solute with a particular chemical structure or site—
carrier—of the membrane must be invoked to explain the total phenomenon. Active transport also requires the concept of carrier-mediated passage across the membrane, but it is clearly distinguished from facilitated diffusion by the movement of the solute in a direction opposite to that of the concentration gradient Thus active transport requires an energy source for the work to be done in moving the solute ‘uphill.’ Endocytosis is a transport mechanism also requiring an expenditure of cellular energy. It entails the local invagination of the cell membrane and subsequent budding off of a vesicle containing fluid, particulate, or solute bound to a membrane protein.
Nonelectrolytes, with the exception of very small or very large molecules, can diffuse passively across biologic barriers at rates proportional to their lipid/water partition coefficients. Very small molecules appear to move faster, and very large ones slower, than would be predicted on the basis of their lipid/water partition coefficients. Weak electrolytes, among them the majority of compounds of pharmacologic interest, diffuse passively across cell membranes at rates which are relatively proportional to their degree of ionization and to the lipid/water partition coefficient of their unionized form. These general principles apply equally to substances of physiologic and pharmacologic importance. Many of the former are nonelectrolytes such as glucose, weak electrolytes such as amino acids or strong electrolytes such as inorganic ions, For these poorly lipid-soluble substances, the specialized transport processes of facilitated diffusion and active transport are available to assist their rapid ingress into or egress from cells. Agents of pharmacologic interest may also use the specialized transport processes that entail reversible interactions with a membrane transporter protein.
Relatively small water soluble molecules and charged ions may diffuse across cell
membranes at rates inconsistent with their nonlipophilic struc
tures. This biotransport may result from direct passage of water through channels within large protein molecules that are embedded in the lipid bilayer and traverse the entire thickness of the membrane. At some biologic barriers the spaces between cells provide a means of more ready passage for some substances. At these barriers, the process of filtration, proportional to a pressure gradient and related to the size of the transferred molecules, can account for the movement of these solutes.
GUIDES FOR STUDY AND REVIEW
What common characteristics do diverse biologic barriers have that account for similarities in solute movement at different sites? What is the general view of the cell membrane and how do its structure and properties regulate solute transport?
What are the mechanisms that account for the transfer of drugs (or other solutes) across biologic barriers? How do these mechanisms differ from one another?
In passive diffusion, what is the force responsible for solute movement and what are the requirements of the process for cellular energy? How do lipid solubility, degree of ionization and molecular size influence the rate of passive diffusion? How does an alteration in pH affect the diffusion of a weak acid? a weak base? Does a change in pH affect the diffusion of a strong acid? a strong base?
In facilitated diffusion, what is the force responsible for solute movement, and what are the requirements of the process for cellular energy? How does facilitated diffusion differ from passive diffusion? What factor determines and what factor limits the rate of facilitated diffusion?
What factor clearly distinguishes the process of active transport from the processes of passive and facilitated diffusion? Why is active transport essential for the life of the cell?
What is endocytosis? What role may this process play in the movement of drugs across biologic barriers?
How does the process of filtration differ from other transport processes with respect to the pathway of solute movement across a cellular barrier? How does the process of filtration differ from other transport processes with respect to the force responsible for transfer across a barrier? How does molecular size influence filtration? At what biologic barrier is filtration an important transport process?
SUGGESTED READING
Ambudkar, S.V., Dey, S., Hrycyna, C.A., Ramachandra, M., Pastan, I. and Gottesman, M.M. Bio-chemical, cellular, and pharmacological aspects of the multidrug transporter. Annu. Rev.
Pharmacol. Toxicol. 39:361–398, 1999.
Ayrton, A. and Morgan, P. Role of transport proteins in drug absorption, distribution and excretion.
Xenobiotica 31:469–497, 2001.
Berne, R.N. and Levy, M.N. (eds) Principles of Physiology (3rd ed.). St Louis: Mosby, 1999.
Clark, D.E. and Grootenhuis, P.D. Predicting passive transport in silico—history, hype, hope.
Current Topics in Medicinal Chemistry 3:1193–1203, 2003.
Cohn, V.H. Transmembrane movement of drug molecules. In: B.N.La Du, H.G.Mandel and E.L.
Way (eds), Fundamentals of Drug Metabolism and Drug Disposition. Melbourne: Krieger Publishing Co., 1979.
Conner, S.D. and Schmid, S.L. Regulated portals of entry into the cell. Nature 422:37–44, 2003.
Davson, H. and Danielli, J.F. Permeability of Natural Membranes. New York: Cambridge University Press, 1952.
Lodish, H.F. and James, E. The assembly of cell membranes. Sci. Am. 240:48, 1979.
How Drugs Reach Their Site of Action
II. Absorption
In order for a drug to exert its characteristic effects, it must reach its site of action. This usually entails movement, since most drugs make initial contact with the body some distance away from where they act. Although the transport processes described in Chapter 4 can account adequately for passage of drugs across any biologic membranes that impede their progress, they can hardly explain movement over a great distance. The forces that drive passive or facilitated diffusion, or active transport and endocytosis, are sufficient only to move solutes across the very short span of cellular membranes themselves. How, then, is the movement of drugs over greater distances accomplished?
Just as oxygen from the lungs or food substances from the intestine gain access to every cell of the organism by way of the bloodstream, so too does the circulatory system serve as the common pathway for carrying drugs from the inner side of a biologic barrier to any tissue or organ. Hence, unless a drug is administered purposely to produce its effect locally or is injected directly into the bloodstream, access to its site of action involves two separate processes. The first of these is absorption, the movement of the solute into the bloodstream from the site of administration. The second process is distribution, the movement of solute from the blood into the tissue (Fig. 5–1).
The rate at which a drug reaches its site of action depends on both its rate of absorption and its rate of distribution. These rates, in turn, are determined by the rates of translocation across the specific barriers interposed between the sites of absorption and action. We have already seen that there are notable similarities in the movement of materials across any biologic barrier. No matter how grossly different the barriers, the mechanisms responsible for solute movement are those that serve to transfer material across any cell membrane. In addition, the principles governing these transport mechanisms apply equally at all barriers. However, barriers may differ with respect to the contribution of filtration, carrier-mediated, and endocytotic transport to the overall translocation process. In addition, the overall movement of materials across different biologic barriers depends upon the anatomic arrangement of the barriers themselves within their contiguous environment.