Goodman & Gilman 5
`The
`Pharmaco I ogi cal
`~-- Basis of ------,
`THERAPEUTICS
`
`eleventh edition
`
`Laurence L Brunton
`John, S. Lazo •· Keith L. Parker
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 1 of 43
`
`

`

`Goodman & Gilman)s
`The
`Pharmacological
`Basis of
`I
`I
`THERAPEUTICS
`
`eleventh edition
`
`Parker, Keith. Goodman and Gilman's the Pharmacological Basis of Therapeutics, edited by Laurence L. Brunton, and JohnS. Lazo, McGraw-Hill Professional
`Publishing, 2005. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/utoronto/detail.action7dociD=4657185.
`Created from utoronto on 2018-06-19 16:45:28.
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 2 of 43
`
`

`

`The McGraw·Hilt Companies ~
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`DOl: 10.1036/0071422803
`
`Parker, Keith. Goodman and Gilman's the Pharmacological Basis of Therapeutics, edited by Laurence L. Brunton, and JohnS. Lazo, McGraw-Hill Professional
`Publishing, 2005. ProQuest Ebook Central, http://ebookcentral. proquestcom/lib/utoronto/detail.action?docl 0=4657185.
`Created from utoronto on 2018·06·19 16:46:28.
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 3 of 43
`
`

`

`SECTION
`General Principles
`
`CHAPTER
`
`1
`
`PHARMACOKINETICS AND
`PHARMACODYNAMICS
`The Dynamics of Drug Absorption, Distribution,
`Action, and Elimination
`
`lain L. 0. Buxton
`
`Numerous factors in addition to a known pharmacologi(cid:173)
`cal action in a specific tissue at a particular receptor con(cid:173)
`tribute to successful drug therapy. When a drug enters
`the body, the body begins immediately to work on the
`drug: absorption, distribution, metabolism (biotransfor(cid:173)
`mation), and elimination. These are the processes of
`pharmacokinetics. The drug also acts on the body, an
`interaction to which the concept of a drug receptor is
`key, since the receptor is responsible for the selectivity
`of drug action and for the quantitative relationship
`between drug and effect. The mechanisms of drug action
`are
`the processes of pharmacodynamics. The time
`course of therapeutic drug action in the body can be
`understood in terms of pharmacokinetics and pharmaco(cid:173)
`dynamics (Figure 1-1).
`
`I. PHARMACOKINETICS: THE DYNAMICS
`OF DRUG ABSORPTION, DISTRIBUTION,
`METABOLISM, AND ELIMINATION
`
`PHYSICOCHEMICAL FACTORS
`IN TRANSFER OF DRUGS
`ACROSS MEMBRANES
`The absorption, distribution, metabolism, and excretion
`of a drug all involve its passage across cell membranes.
`Mechanisms by which drugs cross membranes and the
`
`Parker, Keith. Goodman and Gil man's the Pharmacological Basis of Th erapeutics, edited by Laurence L. Brunton, and John S . Lazo, McGraw-H ill Professional
`
`C
`reate
`
`Pdub1 eeJPilln~ @o§/ti~~E9mf.4"1'1 3t!m~tt~!i90',0~'!YW, 1 ~'900,S~~~.bljJ~~"i~.a<f~"51,0, 1§4~6b)lllPhe McGraw-Hill Companies, Inc. Click here for terms of use.
`rom UtbrdTHO~ o n :to1g:cru-2U'O/:
`: ~~
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 4 of 43
`
`

`

`2
`
`Section I I General Principles
`
`THERAPEUTIC
`SITE OF ACTION
`"Receptors"
`bound ~free
`
`TISSUE RESERVOIRS
`bound~ free
`
`CENTRAL
`COMPARTMENT
`
`UNWANTED SITE
`OF ACTION
`bound ~free
`
`Figure 1-1. The interrelationship of the absorption, distribution, binding, metabolism, and excretion of a drug and its concen(cid:173)
`tration at its sites of action. Possible distribution and binding of metabolites in relation to their potential actions at receptors are not
`depicted.
`
`physicochemical properties of molecules and mem(cid:173)
`branes that influence this transfer are critical to under(cid:173)
`standing the disposition of drugs in the human body. The
`characteristics of a drug that predict its movement and
`availability at sites of action are its molecular size and
`shape, degree of ionization, relative lipid solubility of its
`ionized and nonionized forms, and its binding to serum
`and tissue proteins.
`In most cases, a drug must traverse the plasma mem(cid:173)
`branes of many cells to reach its site of action.
`Although barriers to drug movement may be a single
`layer of cells (intestinal epithelium) or several layers of
`cells and associated extracellular protein (skin), the
`plasma membrane represents the common barrier to
`drug distribution.
`
`Cell membranes are relatively permeable to water either by diffu(cid:173)
`sion or by flow resulting from hydrostatic or osmotic differences
`across the membrane, and bulk flow of water can carry with it drug
`molecules. However, proteins with drug molecules bound to them are
`too large and polar for this type of transport to occur; thus, transmem(cid:173)
`brane movement generally is limited to unbound drug. Paraccllular
`transport through intercellular gaps is sufficiently large that passage
`across most capillaries is limited by blood flow and not by other fac(cid:173)
`tors (see below). As described later, this type of transport is an impor(cid:173)
`tant factor in filtration across glomerular membranes in the kidney.
`Important exceptions exist in such capillary diffusion, however,
`because "tight" intercellular junctions are present in specific tissues,
`and paracellular transport in them is limited. Capillaries of the central
`nervous system (CNS) and a variety of epithelial tissues have tight
`junctions (see below). Bulk flow of water can carry with it small
`water-soluble substances, but bulk-flow transport is limited when the
`molecular mass of the solute exceeds 100 to 200 daltons. Accordingly,
`most large lipophilic drugs must pass through the cell membrane itself.
`
`Cell Membranes. The plasma membrane consists of a bilayer of
`amphipathic lipids with their hydrocarbon chains oriented inward
`to the center of the bilayer to form a continuous hydrophobic
`phase and their hydrophilic heads oriented outward. Individual
`lipid molecules in the bilayer vary according to the particular
`membrane and can move laterally and organize themselves with
`cholesterol (e.g., sphingolipids), endowing the membrane with
`fluidity, flexibility, organization, high electrical resistance, and
`relative impermeability to highly polar molecules . Membrane
`proteins embedded in the bilayer serve as receptors, ion channels,
`or transporters to transduce electrical or chemical signaling path(cid:173)
`ways and provide selective targets for drug actions. These pro(cid:173)
`teins may be associated with caveolin and sequestered within
`caveolae, they may be excluded from caveolae, or they may be
`organized in signaling domains rich in cholesterol and sphingo(cid:173)
`lipid not containing caveolin.
`
`Passive Membrane Transport. Drugs cross membranes either by
`passive processes or by mechanisms involving the active participa(cid:173)
`tion of components of the membrane. In passive transport, the drug
`molecule usually penetrates by diffusion along a concentration gra(cid:173)
`dient by virtue of its solubility in the lipid bilayer. Such transfer is
`directly proportional to the magnitude of the concentration gradient
`across the membrane, to the lipid-water partition coefficient of the
`drug, and to the membrane surface area exposed to the drug. The
`greater the partition coefficient, the higher is the concentration of
`drug in the membrane, and the faster is its diffusion. After a steady
`state is attained, the concentration of the unbound drug is the same
`on both sides of the membrane if the drug is a nonelectrolyte. For
`ionic compounds, the steady-state concentrations depend on the
`electrochemical gradient for the ion and on differences in pH across
`the membrane, which may influence the state of ionization of the
`molecule disparately on either side of the membrane.
`
`Parker, Keith. Goodman and Gilman's the Pharmacological Basis of Therapeutics, edited by Laurence L. Brunton, and JohnS. Lazo, McGraw-H ill Professional
`Publishing, 2005. ProQuest Ebook Central, http://ebookcentral. proquest.com/lib/utoronto/detail.action?docl 0=4657185.
`Created from utoronto on 2018-06-20 07:41:33.
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 5 of 43
`
`

`

`Chapter 1 I Pharmacokinetics and Pharmacodynamics
`
`3
`
`1001 = [HA] +[A"]
`
`[1]
`HA
`Plasma
`pH = 7.4
`
`[1000]
`»A-+ H+
`
`Lipid Mucosal Barrier
`
`Gastric Juice
`
`pH = 1.4
`
`[1]
`HA
`
`[0.001]
`A-+ H+
`
`1.001 = [HA] +[A"]
`
`K+H+
`Weak Acid HA
`nonionized
`ionized
`Figure 1-2. Influence of pH on the distrihutwn of a weak acid
`between plasma and gastric juice separated by a lipid barrier.
`
`pK8 = 4.4
`
`Weak Electrolytes and Influence of pH. Most drugs
`are weak acids or bases that are present in solution as both
`the nonionized and ionized species. The nonionized mole(cid:173)
`cules usually are more lipid-soluble and can diffuse readi(cid:173)
`ly across the cell membrane. In contrast, the ionized mol(cid:173)
`ecules usually are unable to penetrate the lipid membrane
`because of their low lipid solubility.
`Therefore, the transmembrane distribution of a weak elec(cid:173)
`trolyte is determined by its pKa and the pH gradient across the
`membrane. The pKa is the pH at which half the drug (weak
`electrolyte) is in its ionized form. To illustrate the effect of pH
`on distribution of drugs, the partitioning of a weak acid (pK. =
`4.4) between plasma (pH= 7.4) and gastric juice (pH= 1.4) is
`depicted in Figure 1-2. It is assumed that the gastric mucosal
`membrane behaves as a simple lipid barrier that is permeable
`only to the lipid-soluble, nonionized form of the acid. The
`ratio of nonionized to ionized drug at each pH is readily cal(cid:173)
`culated from the Henderson-Hasselbalch equation:
`
`log
`
`[protonated form] = pKa _ pH
`[ unprotonated form]
`
`(1-1)
`
`This equation relates the pH of the medium around the
`drug and the drug ' s acid dissociation constant (pKa) to the
`ratio of the protonated (HA or BH+) and unprotonated (A(cid:173)
`or B) forms, where HA B A- + W (Ka = [A-][W]/[HA])
`describes the dissociation of an acid, and BH+ B B + H+
`(Ka = [B][H+]f[BH+]) describes the dissociation of the
`pronated form of a base.
`Thus, in plasma, the ratio of nonionized to ionized drug
`is 1:1000; in gastric juice, the ratio is 1:0.001. These values
`are given in brackets in Figure 1- 2. The total concentration
`ratio between the plasma and the gastric juice therefore
`would be 1000:1 if such a system came to a steady state. For
`a weak base with a pKa of 4.4, the ratio would be reversed,
`as would the thick horizontal arrows in Figure 1-2, which
`indicate the predominant species at each pH. Accordingly,
`
`at steady state, an acidic drug will accumulate on the more
`basic side of the membrane and a basic drug on the more
`acidic side- a phenomenon termed ion trapping. These
`considerations have obvious implications for the absorption
`and excretion of drugs, as discussed more specifically
`below. The establishment of concentration gradients of
`weak electrolytes across membranes with a pH gradient is a
`physical process and does not require an active electrolyte
`transport system. All that is necessary is a membrane prefer(cid:173)
`entially permeable to one form of the weak electrolyte and a
`pH gradient across the membrane. The establishment of the
`pH gradient, however, is an active process.
`
`Carrier-Mediated Membrane Transport. While passive diffusion
`through the bilayer is dominant in the disposition of most drugs, carrier(cid:173)
`mediated mechanisms also play an important role. Active transporl is
`characterized by a direct requirement for energy, movement against an
`electrochemical gradient, saturability, selectivity, and competitive inhi(cid:173)
`bition by cotransported compounds. Na+,K+-ATPase is an active trans(cid:173)
`port mechanism. Secondary active transport uses the electrochemical
`energy stored in a gradient to move another molecule against a concen(cid:173)
`tration gradient; e.g., the Na+--Ca2+ exchange protein uses the energy
`stored in the Na+ gradient established by the Na+,K+-ATPase to export
`cytosolic Ca2+ and maintain it at a low basal level, approximately 100
`nM in most cells (see Chapter 33); similarly, the Na+-dependent glucose
`transporters SGLTl and SGLT2 move glucose across membranes of
`gastrointestinal (GI) epithelium and renal tubules by coupling glucose
`transport to downhill Na+ flux. Facilitated diffUsion describes a carrier(cid:173)
`mediated transport process in which there is no input of energy, and
`therefore, enhanced movement of the involved substance is down an
`electrochemical gradient as in the permeation of glucose across a mus(cid:173)
`cle cell membrane mediated by the insulin-sensitive glucose transporter
`protein GLUT4. Such mechanisms, which may be highly selective for a
`specific conformational structure of a drug, are involved in the transport
`of endogenous compounds whose rate of transport by passive diffusion
`otherwise would be too slow. In other cases, they function as a barrier
`system to protect cells from potentially toxic substances. Pharmacologi(cid:173)
`cally important transpotters may mediate either drug uptake or efflux
`and often facilitate vectorial transport across polarized cells. An impor(cid:173)
`tant efflux transporter present at many sites is the P-glycoprotein encod(cid:173)
`ed by the multidrug resistance- I (MDRJ) gene. P-glycoprotein localized
`in the enterocyte limits the oral absorption of transported drugs because
`it exports compounds back into the GI tract subsequent to their absorp(cid:173)
`tion by passive diffusion. The P-glycoprotein also can confer resistance
`to some cancer chemotherapeutic agents (see Chapter 51). The impor(cid:173)
`tance of P-glycoprotein in the elimination of drugs is underscored by the
`presence of genetic polymorphisms in MDRJ (see Chapters 2 and 4 and
`Marzolini et al., 2004) that can affect therapeutic drug levels. Transpott(cid:173)
`ers and their roles in drug action are presented in detail in Chapter 2.
`
`DRUG ABSORPTION, BIOAVAILABILITY,
`AND ROUTES OF ADMINISTRATION
`
`Absorption is the movement of a drug from its site of
`administration into the central compartment (Figure 1-1)
`
`Parker, Keith. Goodman and G il man's the Pharmacological Basis of T herapeutics, ed ited by Laurence L. Brunton , and JohnS. Lazo, McG raw-H ill Professional
`Publish ing, 2005. ProQuest Ebook Central , http://ebookcentral. proquestcom/lib/utoronto/detail.action?docl 0 =4657185.
`Created from utoronto on 2018-06-20 07:41 :33.
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 6 of 43
`
`

`

`4
`
`Section I I General Principles
`
`Table 1-1
`Some Characteristics of Common Routes of Drug Administration*
`
`ROUTE
`
`ABSORPTION PATTERN
`
`SPECIAL UTILITY
`
`LIMITATIONS AND PRECAUTIONS
`
`Intravenous
`
`Subcutaneous
`
`Intramuscular
`
`Absorption circumvented
`Potentially immediate
`effects
`Suitable for large volumes
`and for irritating sub(cid:173)
`stances, or complex
`mixtures, when diluted
`Prompt, from aqueous
`solution
`Slow and sustained,
`from repository
`preparations
`Prompt, from aqueous
`solution
`Slow and sustained, from
`repository preparations
`
`Oral ingestion Variable, depends on
`many factors (see text)
`
`Valuable for emergency use
`Permits titration of dosage
`Usually required for high-
`molecular-weight pro(cid:173)
`tein and peptide drugs
`
`Increased risk of adverse effects
`Must inject solutions slowly as a
`rule
`Not suitable for oily solutions or
`poorly soluble substances
`
`Suitable for some poorly solu(cid:173)
`ble suspensions and for
`instillation of slow-release
`implants
`
`Suitable for moderate vol(cid:173)
`umes, oily vehicles, and
`some irritating substances
`Appropriate for self-admin(cid:173)
`istration (e.g., insulin)
`Most convenient and economi(cid:173)
`cal; usually more safe
`
`Not suitable for large volumes
`Possible pain or necrosis from irri(cid:173)
`tating substances
`
`Precluded during anticoagulant
`therapy
`May interfere with interpretation of
`certain diagnostic tests (e.g.,
`creatine kinase)
`Requires patient compliance
`Bioavailability potentially erratic
`and incomplete
`
`'See text for more complete discussion and for other routes.
`
`and the extent to which this occurs. For solid dosage
`forms, absorption first requires dissolution of the tablet
`or capsule, thus liberating the drug. The clinician is con(cid:173)
`cerned primarily with bioavailability rather than absorp(cid:173)
`tion. Bioavailability is a term used to indicate the frac(cid:173)
`tional extent to which a dose of drug reaches its site of
`action or a biological fluid from which the drug has
`access to its site of action. For example, a drug given
`orally must be absorbed first from the stomach and
`intestine, but this may be limited by the characteristics
`of the dosage form and the drug's physicochemical
`properties. In addition, drug then passes through the liv(cid:173)
`er, where metabolism and biliary excretion may occur
`before the drug enters the systemic circulation. Accord(cid:173)
`ingly, a fraction of the administered and absorbed dose
`of drug will be inactivated or diverted before it can
`reach the general circulation and be distributed to its
`sites of action. If the metabolic or excretory capacity of
`the liver for the drug is large, bioavailability will be
`reduced substantially (the first-pass effect). This decrease
`in availability is a function of the anatomical site from
`which absorption takes place; other anatomical, physio-
`
`logical, and pathological factors can influence bioavail(cid:173)
`ability (see below), and the choice of the route of drug
`administration must be based on an understanding of
`these conditions.
`
`Oral (Enteral) versus Parenteral Administration. Often there is a
`choice of the route by which a therapeutic agent may be given, and
`knowledge of the advantages and disadvantages of the different
`routes of administration is then of primary importance. Some char(cid:173)
`acteristics of the major routes employed for systemic drug effect are
`compared in Table 1-l.
`Oral ingestion is the most common method of drug administra(cid:173)
`tion. It also is the safest, most convenient, and most economical.
`Disadvantages to the oral route include limited absorption of some
`drugs because of their physical characteristics (e.g. , water solubili(cid:173)
`ty), emesis as a result of irritation to the GI mucosa, destruction of
`some drugs by digestive enzymes or low gastric pH, irregularities
`in absorption or propulsion in the presence of food or other drugs ,
`and the need for cooperation on the part of the patient. In addition,
`drugs in the GI tract may be metabolized by the enzymes of the
`intestinal flora, mucosa, or liver before they gain access to the
`general circulation.
`The parenteral injection of drugs has certain distinct advantages
`over oral administration. In some instances, parenteral administra(cid:173)
`tion is essential for the drug to be delivered in its active form , as in
`
`Parker, Keith. Goodman and Gilman's the Pharmacological Basis of Therapeutics, edited by Laurence L. Brunton, and JohnS. Lazo, McGraw-Hill Professional
`Publishing, 2005. ProQuest Ebook Central, http://ebookcentral. proquest.com/lib/utoronto/detail.action?docl 0=4657185.
`Created from utoronto on 2018-06-20 07:41:33.
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 7 of 43
`
`

`

`Chapter 1 I Pharmacokinetics and Pharmacodynamics
`
`5
`
`the case of monoclonal antibodies such as infliximab, an antibody
`against tumor necrosis factor a (TNF-a) used in the treatment of
`rheumatoid arthritis. Availability usually is more rapid, extensive,
`and predictable when a drug is given by injection. The effective
`dose therefore can be delivered more accurately. In emergency ther(cid:173)
`apy and when a patient is unconscious, uncooperative, or unable to
`retain anything given by mouth, parenteral therapy may be a neces(cid:173)
`sity. The injection of drugs, however, has its disadvantages: Asepsis
`must be maintained, and this is of particular concern when drugs are
`given over time, such as in intravenous or intrathecal administra(cid:173)
`tion; pain may accompany the injection; and it is sometimes diffi(cid:173)
`cult for patients to perform the injections themselves if self-medica(cid:173)
`tion is necessary.
`
`Oral Ingestion. Absorption from the GI tract is governed by factors
`such as surface area for absorption, blood flow to the site of absorp(cid:173)
`tion, the physical state of the drug (solution, suspension, or solid
`dosage form), its water solubility, and the drug's concentration at
`the site of absorption. For drugs given in solid form, the rate of dis(cid:173)
`solution may be the limiting factor in their absorption, especially if
`they have low water solubility. Since most drug absorption from the
`GI tract occurs by passive diffusion, absorption is favored when
`the drug is in the nonionized and more lipophilic form. Based on the
`pH-partition concept (Figure 1-2), one would predict that drugs that
`are weak acids would be better absorbed from the stomach (pH 1 to
`2) than from the upper intestine (pH 3 to 6), and vice versa for weak
`bases. However, the epithelium of the stomach is lined with a thick
`mucous layer, and its surface area is small; by contrast, the villi of
`the upper intestine provide an extremely large surface area (approxi(cid:173)
`mately 200m2). Accordingly, the rate of absorption of a drug from
`the intestine will be greater than that from the stomach even if the
`drug is predominantly ionized in the intestine and largely nonion(cid:173)
`ized in the stomach. Thus, any factor that accelerates gastric empty(cid:173)
`ing will be likely to increase the rate of drug absorption, whereas
`any factor that delays gastric emptying is expected to have the oppo(cid:173)
`site effect, regardless of the characteristics of the drug. Gastric emp(cid:173)
`tying is influenced in women by the effects of estrogen (i.e., slower
`than in men for premenopausal women and those taking estrogen in
`replacement therapy).
`Drugs that are destroyed by gastric secretions or that cause
`gastric irritation sometimes are administered in dosage forms with
`an enteric coating that prevents dissolution in the acidic gastric
`contents. However, some enteric-coated preparations of a drug
`also may resist dissolution in the intestine, reducing drug absorp(cid:173)
`tion. The use of enteric coatings is nonetheless helpful for drugs
`such as aspirin that can cause significant gastric irritation in many
`patients.
`Controlled-Release Preparations. The rate of absorption of a
`drug administered as a tablet or other solid oral dosage form is
`partly dependent on its rate of dissolution in GI fluids. This is the
`basis for controlled-release, extended-release, sustained-release,
`and prolonged-action pharmaceutical preparations that are designed
`to produce slow, uniform absorption of the drug for 8 hours or
`longer. Such preparations are offered for medications in all major
`drug categories. Potential advantages of such preparations are
`reduction in the frequency of administration of the drug as com(cid:173)
`pared with conventional dosage forms (possibly with improved
`compliance by the patient), maintenance of a therapeutic effect
`overnight, and decreased incidence and/or intensity of both undes(cid:173)
`ired effects (by elimination of the peaks in drug concentration) and
`nontherapeutic blood levels of the drug (by elimination of troughs
`
`in concentration) that often occur after administration of immedi(cid:173)
`ate-release dosage forms.
`Many controlled-release preparations fulfill these expectations and
`may be preferred in some therapeutic situations such as antidepressant
`therapy (Nemeroff, 2003) or treatment with dihydropyridine Ca2+
`entry blockers (see Chapter 32). However, such products have some
`drawbacks. Generally, interpatient variability in terms of the systemic
`concentration of the drug that is achieved is greater for controlled(cid:173)
`release than for immediate-release dosage forms. During repeated
`drug administration, trough drug concentrations resulting from con(cid:173)
`trolled-release dosage forms may not be different from those observed
`with immediate-release preparations, although the time interval
`between trough concentrations is greater for a well-designed con(cid:173)
`trolled-release product. It is possible that the dosage form may fail,
`and "dose dumping" with resulting toxicity can occur because the
`total dose of drug ingested at one time may be several times the
`amount contained in the conventional preparation. Factors that may
`contribute to dose dumping for certain controlled-release preparations
`include stomach acidity and administration along with a high-fat
`meal. Controlled-release dosage forms are most appropriate for drugs
`with short half-lives (<4 hours). So-called controlled-release dosage
`forms are sometimes developed for drugs with long half-lives (> 12
`hours). These usually more expensive products should not be pre(cid:173)
`scribed unless specific advantages have been demonstrated.
`
`Sublingual Administration. Absorption from the oral mucosa has
`special significance for certain drugs despite the fact that the surface
`area available is small. Venous drainage from the mouth is to the supe(cid:173)
`rior vena cava, which protects the drug from rapid hepatic first-pass
`metabolism. For example, nitroglycerin is effective when retained sub(cid:173)
`lingually because it is nonionic and has very high lipid solubility.
`Tims, the drug is absorbed very rapidly. Nitroglycerin also is very
`potent; relatively few molecules need to be absorbed to produce the
`therapeutic effect. If a tablet of nitroglycerin were swallowed, the
`accompanying hepatic metabolism would be sufficient to prevent the
`appearance of any active nitroglycerin in the systemic circulation.
`
`Transdermal Absorption. Not all drugs readily penetrate the intact
`skin. Absorption of those that do is dependent on the surface area over
`which they are applied and their lipid solubility because the epidermis
`behaves as a lipid barrier (see Chapter 63). The dermis, however, is
`freely permeable to many solutes; consequently, systemic absorption
`of drugs occurs much more readily through abraded, burned, or
`denuded skin. Inflammation and other conditions that increase cutane(cid:173)
`ous blood flow also enhance absorption. Toxic effects sometimes
`are produced by absorption through the skin of highly lipid-soluble
`substances (e.g., a lipid-soluble insecticide in an organic solvent).
`Absorption through the skin can be enhanced by suspending the drug
`in an oily vehicle and rubbing the resulting preparation into the skin.
`Because hydrated skin is more permeable than dry skin, the dosage
`form may be modified or an occlusive dressing may be used to facili(cid:173)
`tate absorption. Controlled-release topical patches have become
`increasingly available, including nicotine for tobacco-smoking with(cid:173)
`drawal, scopolamine for motion sickness, nitroglycerin for angina
`pectoris, testosterone and estrogen for replacement therapy, and vari(cid:173)
`ous estrogens and progestins for birth control.
`
`Rectal Administration. The rectal route often is useful when oral
`ingestion is precluded because the patient is unconscious or when
`vomiting is present-a situation particularly relevant to young chil(cid:173)
`dren. Approximately 50% of the drug that is absorbed from the rec-
`
`Parker, Keith . Goodman and G il man's the Pharmacolog ical Basis of T herapeutics, ed ited by Laurence L. Brunton , and JohnS. Lazo, McGraw-H ill Professional
`Publishing, 2005. ProQuest Ebook Central, http://ebookcentral. proquestcom/lib/utoronto/detail. action?docl 0=4657185.
`Created from utoronto on 2018-06-20 07:41:33.
`
`Par Pharmaceutical, Inc. Ex. 1012
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 8 of 43
`
`

`

`6
`
`Section I I General Principles
`
`tum will bypass the liver; the potential for hepatic first-pass metabo(cid:173)
`lism thus is less than that for an oral dose. However, rectal
`absorption often is irregular and incomplete, and many drugs can
`cause irritation of the rectal mucosa.
`
`Parenteral Injection. The major routes of parenteral administration
`are intravenous, subcutaneous, and intramuscular. Absorption from
`subcutaneous and intramuscular sites occurs by simple diffusion
`along the gradient from drug depot to plasma. The rate is limited by
`the area of the absorbing capillary membranes and by the solubility
`of the substance in the interstitial fluid. Relatively large aqueous
`channels in the endothelial membrane account for the indiscriminate
`diffusion of molecules regardless of their lipid solubility. Larger
`molecules, such as proteins, slowly gain access to the circulation by
`way oflymphatic channels.
`Drugs administered into the systemic circulation by any route,
`excluding the intraarterial route, are subject to possible first-pass
`elimination in the lung prior to distribution to the rest of the body.
`The lungs serve as a temporary storage site for a number of agents,
`especially drugs that are weak bases and are predominantly nonion(cid:173)
`ized at the blood pH, apparently by their partition into lipid. The
`lungs also serve as a filter for particulate matter that may be given
`intravenously, and they provide a route of elimination for volatile
`substances.
`Intrave