Chapter 54
`Drug Absorption, Distribution,
`Metabolism, and Excretion
`
`Michael R. Franklin, PhD
`
`INTRODUCTION
`Drugs differ widely in their pharmacodynamic effects and clini-
`cal applications, as well as in penetration, absorption, and usual
`route of administration. They also differ in their distribution
`among the body tissues, and in disposition and mode of termi-
`nation of action. Certain general principles that help explain
`the differences have both pharmaceutical and therapeutic im-
`plications. These principles facilitate an understanding of both
`the features that are common to a class of drugs and the differ-
`ences among the members of that class.
`To have the desired action, a drug must achieve absorption and
`transport to the appropriate tissue or organ, penetrate to the
`responding cell surface or subce!Jular structure, and elicit a re-
`sponse or alter ongoing processes. The drug may be distributed
`simultaneously or sequentially to a number of tissues, be bound
`or stored, be metabolized to inactive or active products, or be
`excreted. The basic entry, movement, and disposition of drugs
`and metabolites within the body are summarized in Figure 54-1.
`Each of the processes or events depicted relates importantly to
`therapeutic and toxic effects of a drug and to the mode of ad-
`ministration, and drug design must take each into account. The
`extent to which aU the components of absorption, distribution,
`metabolism (biotransformation), and elimination apply varies
`enormously with the drug or xenobiotic (the latter being a term
`widely used to refer to not only drugs but any chemical not part
`of the normal biochemistry and physiology of the body) and the
`dose (level of exposure), and to some extent is subject to inter-
`individual variation, the latter often arising from genetic and
`disease state influences.
`Pharmacokinetics is the science that treats the rate and ex-
`tent of absorption, rates of distribution among body compart-
`ments, rate of elimination, and related phenomena. Because of
`its importance, other chapters in this book are devoted to the
`subject. This chapter will consider the physiological bases of
`the processes.
`
`STRUCTURE AND PROPERTIES OF MEMBRANES
`In almost all stages of absorption, distribution, metabolism (bi-
`otransformation), and elimination, a drug must pass through
`several to many biological membranes during the processes.
`Since membranes are traversed in all of these events, a brief
`description of biological membranes and membrane processes
`is in order, as well as the relationship of the physicochemical
`properties of a drug molecule to penetration and transport.
`Numerous sophisticated techniques have established the
`nature of the plasma, mitochondrial, nuclear, and other cell
`membranes. The description of the plasma membrane that
`follows is much oversimplified, but it will suffice to provide a
`
`background for an understanding of drug penetration into and
`through membranes. The cell membrane has been character-
`ized as a bimolecular layer of lipid material entrained between
`two parallel monomolecular layers of protein. However, rather
`than forming a continuous layer, the protein layer comprises
`"islands" sporadically scattered over the surfaces. For many
`proteins, much of the protein is below the surface and within
`the fatty bilayer. The lipid bilayer can be envisaged as a some-
`what orderly, lamellar array of phospholipid molecules associ-
`ated tail-to-tail, each tail being an alkyl chain or steroid group,
`and the heads being polar groups. The disorder that does exist
`is the result of the different degrees of saturation of the fatty
`acids and the interspersed cholesterol molecules that break up
`the close packing of the fatty acid tails. Cholesterol maintains
`the mechanical stability of cell membranes, is a determinant of
`membrane fluidity, and-with relevance to drug passage across
`to water-soluble mol-
`membranes--decreases permeability
`ecules. Moreover, the lamellar portion is penetrated by large
`globular proteins with a highly hydrophobic interior (like the
`lipid layers), and by some fibrous proteins as well.
`The plasma membrane is asymmetrical. The lipid composi-
`tion varies from cell type to cell type and perhaps from site
`to site on the same membrane. There are, for example, differ-
`ences between the membrane of the endoplasmic reticulum
`and the plasma membrane, even though the membranes are
`co-extensive. The membrane surface facing the cytoplasm is
`in phosphatidylethanolamine and phosphatidylserine,
`rich
`while the surface facing the outside is rich in phosphatidylcho-
`line and sphingomyelin. Oligosaccharide chains linked to lipids
`(glycolipids), and oligo- and polysaccharide chains attached to
`proteins (glycoproteins) are confined to non-cytosolic facing
`surfaces. Sugar moieties attached to the outer proteins are most
`often·attached to the asparagine residue. These sugar moieties
`are important to both cellular and immunological recognition
`and adhesion, and they have other functions as well. Where
`membranes are double, the inner and outer layers differ consid-
`erably; the inner and outer membranes of mitochondria have
`strikingly different compositions and properties.
`The cell membrane appears to be perforated by water-fi!Jed
`pores of various sizes, varying from about 4 to 10 A, most of
`which are about 7 A. Probably all major ion (water-filled) chan-
`nels penetrate the large proteins assemblies that traverse the
`membrane. Through these pores pass inorganic ions and sma!J
`organic molecules. Among the common inorganic ions, because
`sodium ions are more hydrated than potassium and chloride
`ions, they are larger and do not pass as freely through the pores
`as do potassium and chloride. Ion (ion plus water) movement
`can be by diffusion down a chemical concentration gradient.
`However, movement of ions through the pores can be con-
`trolled by counterion transport, or expenditure of intrace!Jular
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`1108
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`Absorption:
`Major= alimentary tract (enteran
`Other = respiratory tract, skin
`
`Target organ
`(drug action)
`
`Non-target
`organs
`(drug
`sequestration)
`
`Blood:
`= free drug
`=bound
`drug
`(albumin)
`
`Figure 54-1. Interrelationship of the major components of drug entry, distribution, metabolism, and elimination within the body.
`
`energy-adenosine triphosphate (ATP) hydrolysis-by so-called
`ABC transporters (see Excretion in this chapter). Vascular en-
`dothelium appears to have pores at least as large as 40 A, but
`these seem to be interstitial passages rather than transmem-
`brane pores. Lipid molecules small enough to pass through the
`cell membrane pores may do so, but they have a higher prob-
`ability of entering into the lipid layer (since pores constitute less
`than 1 percent of the cell surface upon which the drug molecule
`impinges); from there these molecules will equilibrate chemical-
`ly with the interior of the cell. Other proteins may be confined to
`one or the other surface and not traverse the membrane. Often
`proteins on the inner surface protein are linked to intracellular
`structural proteins that contribute to cell shape.
`
`DIFFUSION AND TRANSPORT
`Transport is the movement of a drug from one place to another
`within the body. The drug may diffuse freely in uncombined
`form with a kinetic energy appropriate to its thermal environ-
`ment, or it may move in combination with extracellular or cellu-
`lar constituents, sometimes in connection with energy-yielding
`processes that allow the molecule or complex to overcome bar-
`riers to simple diffusion.
`SIMPLE NONIONIC DIFFUSION AND PASSIVE
`TRANSPORT
`Molecules in solution move in a purely random fashion, pro-
`vided they are not charged and moving in an electrical gradient.
`Such random movement is called diffusion; if the molecule is
`uncharged, it is called nonionic diffusion. In a population of drug
`molecules, the probability that during unit time any drug mol-
`ecule will move across a boundary is directly proportional to the
`number of molecules adjoining that boundary and, therefore, to
`the drug concentration. Except at dilutions so extreme that only
`a few molecules are present, the actual rate of movement (mole-
`cules per unit time) is directly proportional to the probability of
`movement and, therefore, to the concentration. Once molecules
`have passed through the boundary to the opposite side, their
`random motion may cause some to return and others to contin-
`ue to move farther away from the boundary. The rate of return is
`lil{ewise proportional to the concentration on the opposite side
`
`of the boundary. It follows that, although molecules are moving
`in both directions, there will be a net movement from the region
`of higher to that of lower concentration, and the net transfer will
`be proportional to the concentration differential. If the bound-
`ary is a membrane, which has both substance and dimension,
`the rate of movement is also directly proportional to the perme-
`ability and inversely proportional to the thickness. These fac-
`tors combine into Fick's law of diffusion:
`
`where Q is the net quantity of drug transferred across the mem-
`brane, tis time, C1 is the concentration on one side and C2 that
`on the other, x is the thickness of the membrane, A is the area,
`and is the diffusion coefficient, related to permeability. Since
`a biological membrane is heterogeneous, with pores of differ-
`ent sizes and probably with varying thickness and composition,
`both and x probably vary from place to place. Nevertheless,
`some mean values can be assumed. It is customary to combine
`the membrane factors into a single constant, called a perme-
`ability constant or coefficient, P, so that P = I x, and A in the
`equation above has unit value. The rate of net transport (diffu-
`sion) across the membrane then becomes:
`
`As diffusion continues, C1 approaches C2, and the net rate,
`dQ/dt, approaches zero in exponential fashion, characteristic
`of a first-order process. Equilibrium is defined as that state in
`which C1 = C2. The equilibrium is, ot course, dynamic, with
`equal numbers of molecules being transported in each direc-
`tion during unit time. If water also is moving through the mem-
`brane, it may either facilitate the movement of drug or impede
`it, according to the relative directions of movement of water
`and drug; this effect of water movement is called solvent drag.
`IONIC OR ELECTROCHEMICAL DIFFUSION
`If a drug is ionized, the transport properties are modified. The
`probability of penetrating the membrane is still a function of
`concentration, but it is also a function of the potential differ-
`ence or electrical gradient across the membrane. A cationic
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`1109
`DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
`often required for the movement of drug metabolites, entities
`drug molecule will be repelled from the positive charge on the
`that generally have less lipid solubility than the parent drug,
`outside of the membrane, and only those molecules with a high
`kinetic energy will pass through the ion barrier. If the cation is
`across cell membranes.
`polyvalent, it may not penetrate at all.
`PINOCYTOSIS AND EXOCYTOSIS
`Once inside the membrane, a cation will be simultaneously
`Many (perhaps all) cells are capable of a type of phagocytosis
`attracted to the negative charge on the intracellular surface of
`called pinocytosis. The cell membrane has been observed to in-
`the membrane and repelled by the outer surface; it is said to be
`vaginate into a sac-like structure containing extracellular mate-
`moving along the electrical gradient. If it is also moving from
`rials and then pinch off the sac at the membrane, so that the sac
`a higher toward a lower concentration, it is said to be moving
`remains as a vesicle or vacuole within the interior of the cell.
`along its electrochemical gradient, which is the sum of the in-
`Because metabolic activity is required and because an extracel-
`fluences of the electrical field and the concentration differential
`lular substance can be transported against an electrochemical
`across the membrane.
`gradient, pinocytosis shows some of tl1e same characteristics
`Once inside the cell, cations will tend to be kept inside by the
`as active transport. However, pinocytosis is relatively slow and
`attractive negative charge on the interior of the cell, and the intra-
`inefficient compared with most active transport, except in GI
`cellular concentration of drug will increase until-by sheer num-
`absorption, where for some xenobiotics pinocytosis may be of
`bers of accumulated drug particles-the rate of outward diffusion
`some importance.
`or mass escape equals that of inward transport. At this point
`It is not !mown to what extent pinocytosis contributes to the
`electrochemical equilibrium is said to have occurred. At electro-
`transport of most drugs, but many macromolecules and even
`chemical equilibrium at body temperature (37•C), ionized drug
`larger particles can be absorbed by the gut. Exocytosis is the
`molecules will be distributed according to the Nem st equation:
`reverse of pinocytosis. Granules, vacuoles, or other organelles
`within the cell move to the cell membrane, fuse with it, and
`extrude their contents into the interstitial space.
`
`PHYSICOCHEMICAL FACTORS IN PENETRATION
`Drugs and other substances may traverse the membrane pri-
`marily eitl1er through the pores, or by movement into the mem-
`brane lipids and subsequent diffusion from the membrane into
`the cytosol or other fluid on the far side of the membrane. The
`physicochemical prerequisites differ according to which route
`is tal{en. To pass through the pores, the diameter of the mol-
`ecule must be smaller than the pore, but the molecu.le can be
`longer than the pore diameter. The probability that a long, thin
`molecule will be suitably oriented, however, is low unless there
`is also bulk flow, and therefore transmembrane passage of such
`molecules is slow.
`Water-soluble molecules with low lipid solubility are usually
`thought to pass through the membrane mainly via the pores. If
`there is a membrane carrier or active-transport system, a low
`solubility of the drug in membrane lipids is no impediment to
`penetration, because the drug-carrier complex is assumed to
`have an appropriate solubility, and energy from an active-trans-
`port system enables the drug to penetrate the energy barrier
`imposed by the lipids. ActuaJly, the lipids are not an important
`energy barrier; rather, the barrier is the force of attraction of
`the solvent water for its dipolar-to-polar solute, so that it is dif-
`ficult for the solute to leave the water and enter the lipid.
`Drugs with a high solubility in the membrane lipids pass eas-
`ily through the membrane. Even when their dimensions are
`small enough to permit passage through pores, lipid-soluble
`drugs primarily pass through the membrane lipids, not only
`because chemical partition favors the lipid phase but also be-
`cause, as mentioned previously, the surface area occupied by
`pores is only a small fraction of the total membrane area.
`LIPID SOLUBILITY AND PARTITION COEFFICIENTS
`Over a century ago, the importance of lipid solubility in the
`penetration and absorption of drugs was being investigated.
`Eventually it was recognized that more important than lipid
`solubility was the lipid-to-water partition (or distribution) co-
`efficient; in other words, a high lipid solubility does not favor
`penetration unless the water solubility is low enough so that
`the drug is not entrained in the aqueous phase. When the water
`solubility of a substance is so low that a significant concentra-
`tion in water or extracellular fluid cannot be achieved, absorp-
`tion may be negligible despite a favorable partition coefficient.
`Ilence, such substances as mineral oil or petrolatum are virtual-
`ly unabsorbed. The optimal partition coefficient for permeation
`of the skin appears to be lower than that for the permeation of
`the cell membrane, perhaps being as low as unity.
`
`± logC0 /C, = ZE/ 61
`where C0 is the molar extracellular and Ci the intracellular con-
`centration, Z is the number of charges per molecule, and E is
`the membrane potential in millivolts. Log CrJCi is positive when
`the molecule is negatively charged and negative when the mol-
`ecule is positively charged.
`FACILITATED DIFFUSION
`Sometimes a substance moves more rapidly through a biologi-
`cal membrane than can be accounted for by the process of sim-
`ple diffusion. This accelerated movement is termed facilitated
`diffusion. It is due to the presence of a special molecule within
`the membrane, called a carrier, with which the transported sub-
`stance combines. There is considered to be greater permeabil-
`ity to the carrier-drug complex than to the drug alone, so that
`the transport rate is enhanced. After the complex has traversed
`the membrane, it dissociates. For the carrier process to be con-
`tinuous, either the carrier must return to the original side of the
`membrane to be used again, or it must constantly be produced
`on one side and eliminated on the other. Many characteristics
`of facilitated diffusion, formerly attributed to ion carriers, can
`be explained by ion exchange. Facilitated diffusion only trans-
`ports a molecule along its electrochemical gradient.
`ACTIVE TRANSPORT
`Active transport can be defined as energy-dependent move-
`ment of a substance through a biological membrane against an
`electrochemical gradient. It is characterized as follows:
`
`1. The substance is transported from a region of lower to
`one of higher electrochemical activity.
`2. Metabolic poisons (that most often reduce ATP concen-
`trations) interfere with transport.
`3. The transport system shows a requirement for specific
`chemical structures.
`4. Closely related chemicals are competitive for the trans-
`port system.
`5. The transport rate approaches an asymptote (i.e., satu-
`rates) as concentration increases.
`Characteristics 3, 4, and 5 are in common with those of carrier-
`mediated facilitated diffusion.
`Many drugs are secreted by active transport from the renal
`tubules into urine, from liver cells into bile or blood, from in-
`testinal cells into the lumen of the gastrointestinal (GI) tract,
`or from the cerebrospinal fluid into blood, but the role of active
`transport of drugs in the d istribution into most body compart-
`ments and tissues has been less extensively documented, al-
`though it is now an active area of research. Active transport is
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`1110
`DIPOLARITY, POLARITY, AND NONIONIC DIFFUSION
`The partition coefficient of a drug depends upon the polarity
`and the size of the molecule. Drugs with a high dipole moment,
`even though nonionized, have low lipid solubility and hence
`penetrate poorly. An example of a highly dipolar substance
`with a low partition coefficient, which does not penetrate into
`cells, is sulfisoxazole. Sulfadiazine is somewhat less dipolar,
`has a chloroform-to-water partition coefficient 10 times that of
`sulfisoxazole, and readily penetrates cells. Ionization not only
`greatly diminishes lipid solubility but also may impede passage
`through charged membranes.
`It is often stated that ionized molecules do not penetrate mem-
`branes, except for ions of small diameter. This is not necessar-
`ily true because of the presence of membrane carriers for some
`ions that effectively shield or neutralize the charge (formation of
`ion pairs). The renal tubular transport systems, which transport
`such obligate ions as tetraethylammonium, probably form ion
`pairs. Furthermore, if an ionized molecule has a large non-polar
`moiety such that appreciable lipid solubility is imparted to the
`molecule despite the charge, the drug may penetrate, though
`usually at a slow rate. Nevertheless, when a drug is a weak acid
`or base, the nonionized form, with a favorable partition coef-
`ficient, passes through a biological membrane so much more
`readily than the ionized form that for all practical purposes, only
`the nonionized form is said to pass through the membrane. This
`has become known as the principle of nonionic diffusion.
`
`ABSORPTION OF DRUGS
`Absorption is the process of movement of a drug from the site
`of application into the extracellular compartment of the .body.
`Inasmuch as there is a great similarity among the various mem-
`branes through which a drug may pass to gain access to the
`extracellular fluid, it might be expected that the particular site
`of application (or route) would make little difference to the suc-
`cessful absorption of the drug. Actually it makes a great deal of
`difference; many factors, other than the structure and composi-
`tion of the membrane, determine the ease with which a drug is
`absorbed. These factors are discussed in the following sections,
`along with an account of the ways that drug formulations can be
`manipulated to alter the ability of a drug to be absorbed readily.
`
`ROUTES OF ADMINISTRATION
`Drugs can be administered by many different routes, includ-
`ing oral, rectal, sublingual or buccal, parenteral, inhalation, and
`topical. The choice of a route depends upon both convenience
`and necessity.
`ORAL ROUTE
`This is obviously the most convenient route for access to the
`systemic circulation, providing that various factors do not mili-
`tate against it. Oral administration does not always give rise to
`plasma concentrations sufficiently high to be effective; some
`drugs are absorbed unpredictably or erratically; patients occa-
`sionally have an absorption malfunction. Drugs cannot be given
`by mouth to patients who have OI intolerance, are being pre-
`pared for anesthesia, or have had 01 surgery. Oral administra-
`tion is also precluded in comatose patients.
`In the drug development setting, Lipinski's "Rule of Five"
`predicts that, in general, an orally active drug has no more than
`one violation of the following criteria:
`• not more than five hydrogen bond donors (oxygen or
`nitrogen atoms with one or more hydrogen atoms)
`• not more than ten (2 x 5) hydrogen bond acceptors (ni-
`trogen or oxygen atoms)
`• a molecular mass not greater than (100 x 5) 500 daltons
`• an octanol-to-water partition coefficient log P not greater
`than 5.
`
`RECTAL ROUTE
`Drugs that are ordinarily administered by the oral route can
`usually be administered by injection or by the alternative lower
`enteral route, through the anal portal into the rectum or lower
`intestine. With regard to the latter, rectal suppositories or re-
`tention enemas were formerly used quite frequently, but their
`popularity has abated somewhat as a result of improvements
`in parenteral preparations. Nevertheless, they continue to be
`valid-and sometimes very important-ways of administering
`a drug, especially in pediatric and geriatric patients, and re-
`tention enema may offer a useful substitute for the oral route.
`However, rectal suppositories may be inadequate when rapid
`absorption and high plasma levels are required,
`SUBLINGUAL OR BUCCAL ROUTE
`Even though an adequate plasma concentration may eventually
`be achievable by the oral route, it may rise much too slowly
`for use in some situations when a rapid response is desired. In
`such situations parenteral therapy is usually indicated. How-
`ever, patients with angina pectoris may get quite prompt relief
`from an acute attack by the sublingual or buccal administra-
`tion of nitroglycerin, so that parenteral administration can be
`avoided. When only smalJ amounts of drugs are required to gain
`access to the blood, the buccal route may be very satisfactory,
`providing the physicochemical prerequisites for absorption by
`this route are present in the drug and dosage form.
`PARENTERAL ROUTES
`These routes, by definition, include any route other than the
`oral-01 (enteral) tract, but in common medical usage the term
`excludes topical administration and includes only various hy-
`podermic routes. Parenteral administration includes the intra-
`venous, intramuscular, and subcutaneous routes. Parenteral
`routes are an option whenever enteral routes are contraindi-
`cated or are inadequate.
`The intravenous route may be preferred on occasion, even
`when a drug may be well absorbed by the oral route. There is
`no delay imposed by absorption before the administered drug
`reaches the circulation, and blood levels rise virtually as rapidly
`as the time necessary to empty the syringe or infusion bottle.
`Consequently, the intravenous route is the preferred route
`when an emergency calls for an immediate response.
`In addition to the rapid rise in plasma concentration of drug,
`another advantage of intravenous administration is the greater
`predictability of the peak plasma concentration, which with
`some drugs can be calculated with a fair degree of precision.
`Smaller doses are generally required by the intravenous than by
`other routes, but this usually affords no advantage, inasmuch
`as the sterile injectable dosage form costs more than enteric
`preparations, and the requirements for medical or paramedi-
`cal supervision of administration also may add to the cost and
`inconvenience.
`Because of the rapidity with which drug enters the circula-
`tion, dangerous side effects to the drug may occur that often
`are not extant by other routes. The principal untoward effect
`is a depression of cardiovascular function. Consequently, some
`drugs must be given quite slowly to avoid vasculotoxic concen-
`trations of drug in the plasma. Acute, serious allergic responses
`are also more likely to occur by the intravenous route than by
`other routes.
`Many drugs are too irritating to be given by the oral, intra-
`muscular, or subcutaneous route, and must of necessity be
`given intravenously. However, such drugs also may cause dam-
`age to the veins (phlebitis) or, if extravasated, cause necrosis
`around the injection site. Consequently, such irritant drugs
`may be diluted in isotonic solutions of saline, dextrose, or other
`media, and given by slow infusion, providing that the slower
`rate of delivery does not negate the purpose of the administra-
`tion in emergency situations.
`Absorption by the intramuscular route is relatively fast, and
`this parenteral route may be used when an immediate effect
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`11 11
`DRUG ABSORPTION. DISTRIBUTION METABOLISM. AND EXCRETION
`Particles larger than 1 micrometer in diameter tend to settle
`is not required but a prompt effect is desirable. Intramuscular
`in the bronchioles and bronchi, whereas particles smaller than
`deposition can also be made of certain repository preparations
`0.5 micrometer fail to settle and mainly are exhaled. Aerosols
`where rapid absorption is not desired. Absorption from an in-
`are employed mostly when the purpose of administration is an
`tramuscular depot is more predictable and uniform than from
`action of the drug upon the respiratory tract itself. An example
`a subcutaneous site. Irritation around the injection site is a fre-
`of a drug commonly given as an aerosol is isoproterenol, which
`quent accompaniment of intramuscular injection, depending
`is employed to relax the bronchioles during an asthma attack.
`upon the drug and other ingredients. Because of the dangers of
`accidental intravenous injection , medical supervision is gener-
`TOPICAL ROUTE
`ally required. Sterilization is necessary.
`Although the stratum corneum is not a membrane in the same
`In subcutaneous administration, the drug is injected into the
`sense as a cell membrane, it offers a barrier to diffusion, which
`connective tissue just below the skin. Absorption is slower than
`is of significance in the topical application of drugs. The stratum
`by the intramuscular route but nevertheless can be prompt
`corneum consists of several layers of dead, keratinized, cutane-
`with some drugs. Often, however, absorption by this route may
`ous epithelial cells enmeshed in a matrix of keratin fibers and
`be no faster than by the oral route. Therefore, when a fairly
`bound together with cementing desmosomes and penetrating
`prompt response is desired with some drugs, the subcutaneous
`tonofibrils of keratin. Varying amounts of lipids and fatty acids
`route may not offer much advantage over the oral route, unless
`from dying cells, sebum, and sweat are contained among the
`for some reason the drug cannot be given orally.
`dead squamous cells. Immediately beneath the layer of dead
`The slower rate of absorption by the subcutaneous route is
`cells and above the viable epidermal epithelial cells is a layer
`usually the reason for choosing the route, and the drugs given
`of keratohyaline granules and various water-soluble substances,
`by this route are usually those for which it is desirable to dis-
`such as amino acids, purines, monosaccharides, and urea.
`tribute the drug's action over several hours, to avoid either too
`Both the upper and lower layers of the stratum corneum are
`intense a response, too short a response, or frequent injections.
`involved in the cutaneous barrier to penetration. The barrier to
`Examples of drugs given by this route are insulin and sodium
`penetration from the surface is in the upper layers for water-
`heparin, neither of which is absorbed orally, and both of which
`soluble substances and the lower layers for lipid-soluble sub-
`should be absorbed slowly over many hours. In the treatment
`stances, and the barrier to the outward movement of water is
`of asthma, epinephrine is usually given subcutaneously to avoid
`the dangers of rapid absorption and consequent dangerous
`in the lowest layer.
`Topical administration is employed to deliver a drug at, or
`cardiovascular effects. Many repository preparations, includ-
`immediately beneath, the point of application. Although occa-
`ing tablets or pellets, are given subcutaneously. As with other
`sionally enough drug is absorbed into the systemic circulation
`parenteral routes, irritation may occur. Sterile preparations are
`to cause systemic effects, absorption is too erratic for the topi-
`also required. However, medical supervision is not always re-
`cal route to be used routinely for systemic therapy. However,
`quired, and self-administration by this route is customary with
`various transdermal preparations are employed quite success-
`certain drugs, such as insulin.
`fully for systemic use. A large number of topical medicaments
`Intradermal injection, in which the drug is injected into the
`are applied to the skin, although topical drugs are also applied
`dermis instead of below it, is rarely used, except in certain di-
`to the eye, nose, throat, ear, vagina, etc.
`agnostic and test procedures, such as screening for allergic or
`In humans, percutaneous absorption probably occurs main-
`local irritant responses.
`ly from the surface. Absorption tluough the hair follicles oc-
`Occasionally, even by the intravenous route, it is not pos-
`curs, but the follicles in humans occupy too small a portion of
`sible, practical, or safe to achieve plasma concentrations high
`the total integument to be of primary importance. Absorption
`enough so that an adequate amount of drug penetrates into spe-
`through sweat and sebaceous glands generally appears to be mi-
`cial compartments (e.g., the cerebrospinal fluid) or various cav-
`nor. When the medicament is rubbed on vigorously, the amount
`ities (e.g., the pleural cavity). The brain is especially difficult to
`of the preparation that is forced into the hair follicles and glands
`penetrate with water-soluble drugs. The name blood-brain bar-
`is increased. Rubbing also forces some material through the
`rier is applied to the impediment to penetration. When drugs do
`stratum corneum without molecular dispersion and diffusion
`penetrate, the choroid plexus often secretes them back into the
`through the barrier. When the skin is diseased or abraded, the
`blood very rapidly, so that adequate levels of drugs in the ce-
`cutaneous barrier may be disrupted or defective, so that per-
`rebrospinal fluid can be difficult to achieve. Consequently, in-
`cutaneous absorption may be increased. Since much of a drug
`trathecal or intraventricular administration may be indicated.
`that is absorbed through the epidermis diffuses into the circula-
`Body cavities such as the pleural cavity are normally wet-
`tion without reaching a high concentration in some