Transfer across biological membranes

The processes of absorption, distribution, biotransformation, and elimination of a particular substance involve the transfer or movement of a drug across biological membranes. Therefore, it is important to understand those properties of cell membranes and the intrinsic properties of drugs which affect movement. Although drugs may gain entry into the body by passage through a single layer of cells, such as the intestinal epithelium, or through multiple layers of cells, such as the skin, the blood cell membrane is a common barrier to all drug entry and therefore is the most appropriate membrane for general discussion of cellular membrane structure. The cellular blood membrane consists of a phospholipid bilayer of 7 to 9 nm thickness with hydrocarbon chains oriented inward and polar head groups oriented outward. Interspersed between the lipid bilayer are proteins, which may span the entire width of the membrane permitting the formation of aqueous pores.2 These proteins act as receptors in chemical and electrical signaling pathways and also as specific targets for drug actions.3 The lipids in the cell membrane may move laterally, confering fluidity at physiological temperatures and relative impermeability to highly polar molecules. The fluidity of plasma membranes is largely determined by the relative abundance of unsaturated fatty acids. Between cell membranes are pores which may permit bulk flow of substances. This is considered to be the main mechanism by which drugs cross the capillary endothelial membranes, except in the central nervous system which possesses tight junctions that limit intercellular diffusion.3

Physicochemical properties of a drug also affect its movement across cell membranes. These include its molecular size and shape, solubility, degree of ionization, and relative lipid solubility of its ionized and nonionized forms. Another factor to consider is the extent of protein binding to plasma and tissue components. Although such binding is reversible and usually rapid, only the free unbound form is considered capable of passing through biological membranes.

Drugs cross cell membranes through passive and active or specialized processes. Passive movement across biological membranes is the dominant process in the absorption and distribution of drugs. In passive transfer, hydrophobic molecules cross the cell membrane by simple diffusion along a concentration gradient. In this process there is no expenditure of cellular energy. The magnitude of drug transfer in this manner is dependent on the magnitude of the concentration gradient across the membrane and the lipid:water partition coefficient. Once steady state has been reached, the concentration of free (unbound) drug will be the same on both sides of the membrane. The exception to this situation is if the drug is capable of ionization under physiological conditions. In this case, concentrations on either side of the cell membrane will be influenced by pH differences across the membrane. Small hydrophilic molecules are thought to cross cell membranes through the aqueous pores.4 Generally, only unionized forms of a drug cross biological membranes due to their relatively high lipid solubility. The movement of ionized forms is dependent on the pKa of the drug and the pH gradient. The partitioning of weak acids and bases across pH gradients may be predicted by the Henderson-Hasselbalch equation. For example, an orally ingested weakly acidic drug may be largely unionized in the acidic environs of the stomach but ionized to some degree at the neutral pH of the plasma. The pH gradient and difference in the proportions of ionized/ nonionized forms of the drug promote the diffusion of the weak acid through the lipid barrier of the stomach into the plasma.

Water moves across cell membranes either by the simple diffusion described above or as the result of osmotic differences across membranes. In the latter case, when water moves in bulk through aqueous pores in cellular membranes due to osmotic forces, any molecule that is small enough to pass through the pores will also be transferred. This movement of solutes is called filtration. Cell membranes throughout the body possess pores of different sizes; for example, the pores in the kidney glomerulus are typically 70 nm, but the channels in most cells are < 4 nm.2

The movement of some compounds across membranes cannot be explained by simple diffusion or filtration. These are usually high molecular weight or very lipid soluble substances. Therefore, specialized processes have been postulated to account for the movement. Active processes typically involve the expenditure of cellular energy to move molecules across biological membranes. Characteristics of active transport include selectivity, competitive inhibition, saturability, and movement across an electrochemical or concentration gradient. The drug complexes with a macromolecular carrier on one side of the membrane, traverses the membrane and is released on the other side. The carrier then returns to the original surface. Active transport processes are important in the elimination of xenobiotics. They are involved in the movement of drugs in hepatocytes, renal tubular cells and neuronal membranes. For example, the liver has four known active transport systems, two for organic acids, one for organic bases, and one for neutral organic compounds.2 A different specialized transport process is termed facilitated diffusion. This transport is similar to the carrier mediated transport described above except that no active processes are involved. The drug is not moved against an electrochemical or concentration gradient and there is no expenditure of energy. A biochemical example of such transport is the movement of glucose from the gastrointestinal tract through the intestinal epithelium. Absorption

In order for a drug to exert its pharmacological effect, it must first gain entry into the body, be absorbed into the bloodstream and transported or distributed to its site of action. This is true except in the case of drugs that exert their effect locally or at the absorption site. The absorption site, or port of entry, is determined by the route of drug administration.

Routes of administration are either enteral or parenteral. The former term denotes all routes pertaining to the alimentary canal. Therefore, sublingual, oral, and rectal are enteral routes of administration. All other routes, such as intravenous, intramuscular, subcutaneous, dermal, vaginal, and intraperitoneal, are parenteral routes.

Absorption describes the rate and extent to which a drug leaves its site of administration and enters the general circulation. Factors which, therefore, affect absorption include: the physicochemical properties of the drug which determine transfer across cell membranes as described earlier; formulation or physical state of the drug; site of absorption; concentration of drug; circulation at absorption site; and area of absorbing surface.

Absorption of drug may occur at any point along the tract including the mouth, stomach, intestine, and rectum. Because the majority of drugs are absorbed by passive diffusion, the nonionized, lipid soluble form of the drug is favored for rapid action. Therefore, according to the Henderson-Hasselbalch equation, the absorption of weak acids should be favored in the stomach and the absorption of weak bases in the alkaline environment of the small intestine. However, other factors such as relative surface area will influence absorption. The stomach is lined by a relatively thick mucus-covered membrane to facilitate its primary function of digestion. In comparison, the epithelium of the small intestine is thin, with villi and microvilli providing a large surface area to facilitate its primary function of absorption of nutrients. Therefore, any factor that increases gastric emptying will tend to increase the rate of drug absorption, regardless of the ionization state of the drug.

The G.I. tract possesses carrier mediated transport systems for the transfer of nutrients and electrolytes across the gastric wall. These systems may also carry drugs and other xenobiotics into the organism. For example, lead is absorbed by the calcium transporter.5 Absorption also depends on the physical characteristics of a drug. For example, a highly lipid soluble drug will not dissolve in the stomach. In addition, solid dosage forms will have little contact with gastric mucosa and the drug will not be absorbed until the solid is dissolved. Further, the particle size affects absorption, since dissolution rate is proportional to particle size.6 Compounds that increase intestinal permeability or increase the residence time in the intestine by altering intestinal motility will thereby increase absorption of other drugs through that segment of the alimentary canal.

Once a drug has been absorbed through the G.I. tract, the amount of the compound that reaches the systemic circulation depends on several factors. The drug may be biotransformed by the G.I. cells or removed by the liver through which it must pass. This loss of drug before gaining access to the systemic circulation is known as the first pass effect.

Although oral ingestion is the most common route of G.I. absorption, drugs may be administered sublingually. Despite the small surface area for absorption, certain drugs which are nonionic and highly lipid soluble are effectively absorbed by this route. The drugs nitroglycerin and buprenorphine are administered by this route. The blood supply in the mouth drains into the superior vena cava and because of this anatomic characteristic, drugs are protected from first pass metabolism by the liver.

Although an uncommon route by which abused drugs are self-administered, rectal administration is used in medical practice when vomiting or other circumstances preclude oral administration. Approximately 50% of the drug that is absorbed will bypass the liver.3 The disadvantage of this route for drug absorption is that the process is often incomplete and irregular and some drugs irritate the mucosal lining of the rectum. Pulmonary

Gases, volatile liquids, and aerosols may be absorbed through the lungs. Access to the circulation by this route is rapid because of the large surface area of the lungs and extensive capillary network in close association with the alveoli. In the case of absorption of gases and volatilizable liquids, the ionization state and lipid solubility of the substance are less important than in G.I. absorption. This is because diffusion through cell membranes is not the rate limiting step in the absorption process. The reasons include low volatility of ionized molecules, the extensive capillary network in close association with the alveoli resulting in a short distance for diffusion, and the rapid removal of absorbed substances by the blood. Some substances may not reach the lungs due to being deposited and absorbed in the mucosal lining of the nose.

Drugs may be atomized or volatilized and inhaled as droplets or particulates in air, a common example being the smoking of drugs. The advantages of this route include rapid transport into the blood, avoidance of first pass hepatic metabolism, and avoidance of the medical problems associated with other routes of illicit drug administration. Disadvantages include local irritant effect on the tissues of the nasopharynx and absorption of particluate matter in the nasopharynx and bronchial tree. For a drug to be effectively absorbed it should reach the alveoli. However, absorption of particulate matter is governed by particulate size and water solubility. Particles with diameters >5 |im are usually deposited in the nasopharyngeal region;2 particles in the 2 to 5 |im range are deposited in the tracheobronchiolar region and particles 1 |im and smaller reach the alveolar sacs.

The skin is impermeable to most chemicals. For a drug to be absorbed it must pass first through the epidermal layers or specialized tissue such as hair follicles or sweat and sebaceous glands. Absorption through the outer layer of skin, the stratum corneum, is the rate limiting step in the dermal absorption of drugs. This outer layer consists of densely packed keratinized cells and is commonly referred to as the "dead" layer of skin because the cells comprising this layer are without nuclei. Drug substances may be absorbed by simple diffusion through this layer. The lower layers of the epidermis, and the dermis, consist of porous nonselective cells which pose little barrier to absorption by passive diffusion. Once a chemical reaches this level, it is then rapidly absorbed into the systemic circulation because of the extensive network of venous and lymphatic capillaries located in the dermis. Drug absorption through the skin depends on the characteristics of the drug and on the condition of the skin. Since the stratum corneum is the main barrier to absorption, damage to this area by sloughing of cells due to abrasion or burning enhances absorption, as does any mechanism which increases cutaneous blood flow. Hydration of the stratum corneum also increases its permeability and therefore enhances absorption of chemicals. Parenteral Injection

Drugs are often absorbed through the G.I. tract, lungs, and skin but many illicit drugs have historically been self-administered by injection. These routes typically include intravenous, intramuscular, and subcutaneous administration. The intravenous route of administration introduces the drug directly into the venous bloodstream, thereby eliminating the process of absorption altogether. Substances that are locally irritating may be administered intravenously since the blood vessel walls are relatively insensitive. This route permits the rapid introduction of drug to the systemic circulation and allows high concentrations to be quickly achieved. Intravenous administration may result in unfavorable physiological responses because once introduced, the drug cannot be removed. This route of administration is dependent on maintaining patent veins and can result in extensive scar tissue formation due to chronic drug administration. Insoluble particulate matter deposited in the blood vessels is another medical problem associated with the intravenous route.

Intramuscular and subcutaneous administration involves absorption from the injection site into the circulation by passive diffusion. The rate of absorption is limited by the size of the capillary bed at the injection site and by the solubility of the drug in the interstitial fluid.3 If blood flow is increased at the administration site, absorption will be increased. Distribution

After entering circulation, drugs are distributed throughout the body. The extent of distribution is dependent on the physicochemical properties of the drug and physiological factors. Drugs cross cell membranes throughout the body by passive diffusion or specialized transport processes. Small water soluble molecules and ions cross cell membranes through aqueous pores whereas lipid soluble substances diffuse through the membrane lipid bilayer. The rate of distribution of a drug is dependent on blood flow and the rate of diffusion across cell mebranes of various tissues and organs. The affinity of a substance for certain tissues also affects the rate of distribution.

Because only unbound drug (the free fraction) is in equilibrium throughout the body, disposition is affected by binding to or dissolving in cellular constituents. While circulating in blood, drugs may be reversibly bound to several plasma proteins. For example, basic compounds often bind to a1-acid glycoprotein; acidic compounds bind to albumin. The extent of plasma protein binding varies among drugs, nicotine is 5% bound whereas the barbiturate, secobarbital, is 50% bound, and the benzodiazepine, diazepam is 96% bound.7 The fraction of drug that is bound is governed by the drug concentration, its affinity for binding sites, and the number of binding sites. At low drug concentrations, the fraction bound is a function of the number of binding sites and the dissociation constant, a measure of binding affinity. When drug concentrations exceed the dissociation constant, concentration also governs the amount of protein binding. Therefore, published protein binding fractions for drugs only apply over a certain concentration range, usually the therapeutic concentration. Plasma protein binding limits the amount of drug entering tissues. Because plasma protein binding of drugs is relatively non-selective, drugs and endogenous substances compete for binding sites, and drug displacement from binding sites by another substance can contribute to toxicity by increasing the free fraction. Binding to Tissue Constituents

In addition to binding to plasma proteins, drugs may bind to tissue constituents. The liver and kidney have a large capacity to act as storage depots for drugs. The mechanisms responsible for transfer of many drugs from the blood appear to be active transport processes.2 Ligandin, a cytoplasmic liver protein, has a high affinity for many organic acids while metallothionein binds metals in the kidney and liver.

Lipid soluble drugs are stored in neutral fat by dissolution. Since the fat content of an obese individual may be 50% body weight, it follows that large amounts of drug can be stored in this tissue. Once stored in fat, the concentration of drug is lowered throughout the body, in the blood and also in target organs. Any activity, such as dieting or starvation, which serves to mobilize fat, could potentially increase blood concentrations and hence contribute to an increase in the risk of drug toxicity.

Drugs may also be stored in bone. Drugs diffuse from the extracellular fluid through the hydration shell of the hydroxyapatite crystals of the bone mineral. Lead, fluoride, and other compounds may be deposited and stored in bone. Deposition may not necessarily be detrimental. For example, lead is not toxic to bone tissue. However, chronic fluoride deposition results in the condition known as skeletal fluorosis. Generally, storage of compounds in bone is a reversible process. Toxicants may be released from the bone by ion exchange at the crystal surface or by dissolution of the bone during osteoclastic activity. If osteolytic activity is increased, the hydroxyapatite lattice is mobilized resulting in an increase in blood concentrations of any stored xenobiotics. Blood Brain Barrier

The blood-brain barrier is often viewed as an impenetrable barrier to xenobiotics. However, this is not true and a more realistic representation is as a site that is less permeable to ionized substances and high molecular weight compounds than other membranes. Many toxicants do not enter the brain because the capillary endothelial cells are joined by tight junctions with few pores between cells; the capillaries of the central nervous system are surrounded by glial processes; and the interstitial fluid of the CNS has a low protein concentration. The first two anatomical processes limit the entry of small- to medium-sized water soluble molecules, whereas the entry of lipid soluble compounds is limited by the low protein content which restricts paracellular transport. It is interesting to note that the permeability of the brain to toxicants varies from area to area. For example, the cortex, area postrema, and pineal body are more permeable than other regions.2 This may be due to differences in blood supply or the nature of the barrier itself. Entrance of drugs into the brain is governed by the same factors that determine transfer across membranes in other parts of the body. Only the unbound fraction is available for transfer and lipid solubility and the degree of ionization dictate the rate of entry of drugs into the brain. It should be noted that the blood-brain barrier is not fully developed at birth. In animal studies, morphine has been found to be 3 to 10 times more toxic to newborns than adults.8 Pregnancy

During pregnancy, drugs may also be distributed from the mother to the fetus by simple diffusion across the placenta. The placenta comprises several cell layers between the maternal and fetal circulations. The number of layers varies between species and state of gestation. The same factors govern placental drug transfer as movement by passive diffusion across other membranes. The placenta plays an additional role in preventing transfer of xenobiotics to the fetus by possessing biotransformation capabilities.

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