APPLIED
`BIOPHARMACEUTICS
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`&PHARMACOK|NET|CS
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`FIFTH EDITION
`
`LEON SHARGEL. PhD, RPh
`Vice President, Biopharmaceutics
`Eon Labs, Inc.
`Wilson, North Carolina
`
`Adjunct Associate Professor
`School of Pharmacy
`University of Mar§1and
`Baltimore, Maryland
`
`SUSANNA WU—PONG PhD. RPh
`Associate Professor
`
`Department of Pharmaceutics
`Medical College of Virginia Campus
`Virginia’Commonwealth University
`Richmond, Virginia
`
`ANDREW B.C. YU PhD. RPh
`Registered Pharmacist
`Gaithersburg, MD
`Formerly Associate Professor of Pharmaceutics
`Albany College of Pharmacy
`Present Affiliation: HFD-520, CDER, FDA*
`
`*The content of this book represents the personal views of the authors and not that of the FDA.
`
`McGraw—Hill
`
`Medical Publishing Division
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`New York Chicago San Francisco Lisbon London Madrid Mexico City Milan
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`RB Ex. 2036
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014—00325 Page 1
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`Page 1
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`RB Ex. 2036
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`

`

`The McGraw-Hm‘ Companies
`
`Applied Biopharmaceutics and Pharmacokincfics, Fifth Edition
`
`
`
`Copyright © 2005 by The McGraw—Hill Companies, Inc. Copyright © 1999, 1993 by Apple ton
`& Lange; copyright © 1985, 1980 by Appleton-Century—Crofts. All rights reserved. Printed
`in the United States of America. Except as permitted under the United States copyright
`Act of 1976, no part of this publication may be reproduced or distributed in any form or
`by any means, or stored in a data base or retrieval system, without the prior written per-
`mission of the publisher.
`
`
`
`
`
`234567890 DOC/DOC 098765
`
`ISBN 0-07—137550—3
`
`This book was set in New Baskerville by TechBooks.
`The editors were Michael Brown and Christie Naglieri.
`The production service was TechBooks.
`The production supervisor was Phil Galea.
`The cover designer was Kelly Parr.
`RR Donnelley was printer and binder.
`
`This book is printed on acid-free paper.
`
`Library of Congress Cataloging-in-Publicafion Data
`
`Shargel, Leon, 1941—
`Applied biopharmaceutics 8c pharmacokinetics/Leon Shargel, Susanna Wu-Pong,
`Andrew B.C. Yu. -—5th ed.
`p. ; cm.
`Includes bibliographical references and index.
`ISBN 0-07-137550-3
`
`I. Title: Applied biopharmaceutics and
`2. Pharmacokinetics.
`1. Biopharmaceutics.
`pharmacokinetics.
`II. Wu—Pong, Susanna.
`III. Yu, Andrew B. C.,
`1945— IV. Title.
`
`2. Models, Chemical.
`1. Biopharmaceutics.
`[DNLMz
`QV 38 $531a 2004] RM301.4.S52 2004
`615'.7—dc22
`
`3. Phannacokinetics.
`
`2004044993
`
`Please tell the authors and publisher what you think of this book by sending your
`comments to pharmacy@mcgraw—hill.c0m. Please put the author and title of the
`book in the subject line.
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`I II|
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`I
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`Page 2
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`Page 2
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`370
`
`
`PharmGKB: www.pharmgkb.org PharmGKB is an integrated resource about how variation in human
`genes leads to variation in response to drugs.
`
`Raimundo S, Fischer], Eichelbaum M, Griese E—U, Schwab M, Zanger UM: Elucidation of the genetic
`
`basis of the common “intermediate metabolizer" phenotype for drug oxidation by CYP2D6'
`
`Pharmacagenetics 10:1—5, 2000
`
`Synold TW, Dussault I, Forman BM: The orphan nuclear receptor SXR coordinately regulates drug me-
`
`tabolism and efllux. Nature Med 7(5), 2001
`
`Page 3
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`Page 3
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`l3
`
`PHYSIOLOGIC
`
`FACTORS RELATED TO
`
`DRUG ABSORPTION
`
`371
`
`Drugs may be given by parenteral, enteral, inhalation, transdermal (percutaneous),
`or intranasal route for systemic absorption. Each route of drug administration has
`certain advantages and disadvantages. Some characteristics of the more common
`routes of drug administration are listed in Table 13.1. The systemic availability and
`onset of drug action are affected by blood flow to the administration site, the physi-
`' cochemical characteristics of the drug and the drug product, and by any pathophys—
`iologic condition at the absorption site.
`Many drugs are not administered orally because of drug instability in the
`gastrointestinal tract or drug degradation by the digestive enzymes in the intestine.
`For example, erythropoietin and human growth hormone (somatrophin) are ad-
`ministered intramuscularly, and insulin is administered subcutaneously or intramus-
`cularly, because of the potential for degradation of these drugs in the stomach or
`intestine. Biotechnology products (Chapter 18) are often too labile to be admin-
`istered orally and therefore are usually given parenterally. Drug absdrption after
`subcutaneous injection is slower than intravenous injection. Pathophysiologic
`
`The systemic absorption of a drug is dependent on (1) the physicochemical prop-
`erties of the drug, (2) the nature of the drug product, and (3) the anatomy and
`physiology of the drug absorption site. All of these considerations are important in
`the manufacture and biopharmaceutic evaluation of drug products (Chapter 14).
`Proper drug product selection requires a thorough understanding of the physio-
`logic and pathologic factors affecting drug absorption to assure therapeutic efficacy
`and to avoid potential drug—drug and drug—nutrient interactions. This chapter will
`focus on the anatomic and physiologic considerations for the systemic absorption
`of a drug.
`
`\
`
`ROUTE OF DRUG mmIsmATION
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`Page 4
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`372
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`
`CHAPTERB. PHYSIOLQGEZLACTORS RELATE_D TO DRUG ABSORPTION _
`
`TABLE 13.!
`Common Routes of Drug Administration
`BIOAVAILABIEITY
`ROUTE
`DISADVANTAGES
`ADVANTAGES
`Parenteral Routes
`Intravenous bolus (IV)
`
`Drug is given for immedi—
`ate effect
`
`Increased chance for
`adverse reaction.
`Possible anaphylaxis.
`
`Complete (IOO%] systemic
`drug absorption.
`Rate of bioavailability con-
`sidered instantaneous.
`Complete (IOO%I systemic
`drug absorption.
`Rate of drug absorption
`controlled by infusion
`rate.
`
`Rapid from aqueous
`solution.
`Slow absorption from non»
`aqueous (oil) solutions.
`
`Prompt from aqueous solu-
`tion.
`Slow absorption from
`repository formulations.
`
`Plasma drug levels more
`precisely controlled.
`May inject large fluid vol-
`umes.
`
`May use drugs with poor
`lipid solubility and/or irri-
`tating drugs.
`Easier to inject than intra
`venous injection.
`Larger volumes may be
`used compared to sub
`cutaneous solutions.
`
`Generally, used for insulin
`injection.
`
`Intravenous infusion
`(IV inf)
`
`Intramuscular injection
`l|IV|l
`
`Subcutaneous injection
`(SCI
`
`Enteral Routes
`Buccal or sublingual (SL)
`
`Oral (PO)
`
`Rectal (PR)
`
`Other Routes
`Transdermal
`
`Rapid absorption from lipid-
`soluble drugs.
`
`N0 "first-pass" effects.
`
`Absorption may vary.
`Generally, slower absorp-
`tion rate compared to IV
`bolus or IM injection.
`
`Safest and easiest route of
`drug administration.
`May use immediate-release
`and modified-release
`drug products.
`
`Absorption may vary from
`suppository.
`More reliable absorption
`from enema (solution).
`
`Useful when patient can-
`not swallow medication.
`Used for local and systemic
`effects.
`
`Slow absorption, rate may
`vary.
`Increased absorption with
`occlusive dressing.
`
`Transdermal delivery system
`(patch) is easy to use.
`Used for lipid-soluble drugs
`with low dose and low
`MW.
`
`Inhalation
`and intranasal
`
`Rapid absorption.
`Total dose absorbed is vari-
`able.
`
`May be used for local or
`systemic effects.
`
`
`
`Requires skill in insertion of
`infusion set.
`Tissue damage at site of
`injection (infiltration,
`necrosis, or sterile
`abscess].
`
`Irritating drugs may be very
`painful.
`Different rates of absorp-
`tion depending on mus-
`cle group injected and
`blood flow.
`Rate of drug absorption
`depends on blood flow
`and injection volume.
`
`Some drugs may be swal—
`lowed.
`
`Not for most drugs or
`drugs with high doses.
`Some drugs may have
`erratic absorption, be
`unstable in the gastoin-
`testinal tract, orbe
`metabolized by liver prior
`to systemic absorption.
`Absorption may be erratic.
`Suppository may migrate to
`different position.
`Some patient discomfort.
`
`SOme irritation by patch or
`drug.
`.
`Permeability of skin variable
`with condition, anatomic
`site, age. and gender.
`Type of cream or ointment
`base affects drug release
`and absorption.
`Particle size of drug deter-
`mines anatomic place-
`ment in respiratory tract.
`May stimulate coLigh reflex.
`Some drug may be
`swalloWed.
`
`
`
`
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`Page 5
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`

`
`PHYSIOLOGIEAFACTORS RELATED TO DRUG ABSORPTION CHAPTERB:
`
`373
`
`conditions such as burns will increase the permeability of drugs across the skin
`compared with normal intact skin.
`When a drug is administered by an extravascular route of administration (eg,
`oral, topical, intranasal, inhalation, rectal), the drug must first be absorbed into
`the systemic circulation and then diffuse or be transported to the site of action
`before eliciting biological and therapeutic activity. The general principles and
`kinetics of absorption from‘ these extravascular sites follow the same principles as
`oral dosing, although the physiology of the site of administration differs.
`
`NATURE OF CELL MEMBRANES
`
`and certain charged ions.
`
`Many drugs administered by extravascular routes are intended for local effect. Other
`drugs are designed to be absorbed from the site of administration into the systemic
`circulation. For systemic drug absorption, the drug must cross cellular membranes.
`After oral administration, drug molecules must cross the intestinal epithelium by
`going either through or between the epithelial cells to reach the systemic circula-
`tion. The permeability of a drug at the absorption site into the systemic circulation
`is intimately related to the molecular structure of the drug and to the physical and
`biochemical properties of the cell membranes. Once in the plasma, the drug may
`have to cross biological membranes to reach the site of action. Therefore, biological
`membranes potentially pose a significant barrier to drug delivery.
`Tramcellular absmptian is the process of drug movement across a cell. Some po-
`lar molecules may not be able to traverse the cell membrane but, instead, go
`through gaps or tight junctions between cells, a process known as paracellular drug
`absmption. Figure 13—1 shows the difference between the two processes. Some drugs
`are probably absorbed by a mixed mechanism involving one or more processes.
`Membranes are major structures in cells-Surrounding the entire cell (plasma
`membrane) and acting as a boundaiy between the' cell and the interstitial fluid. In
`addition, membranes enclose most of the cell organelles (eg, the mitochondrion
`membrane). Functionally, cell membranes are semipermeable partitions that act as
`selective barriers to the passage of molecules. Water, some selected small molecules,
`and lipid-soluble moleculespass through such membranes, whereas highly charged
`molecules and large molecules, such as proteins and protein-bound drugs, do not.
`The transmembrane movement of drugs is influenced by the composition and .
`structure of the plasma membranes. Cell membranes are generally thin, approxi—
`mately 70 to 100 A in thickness. Cell membranes are composed primarily of phos-
`pholipids in the form of a bilayer interdispersed with carbohydrates and protein
`groups. There are several theories as to the structure of the cell membrane. The
`lipid bilayer or unit membrane theory, originally proposed by Davson and Danielli
`(1952), considers the plasma membrane to be composed of two layers of phos—
`pholipid between two surface layers of proteins, with the hydrophilic “head” groups
`of. the phospholipids facing the protein layers and the hydrophobic “tail” groups of
`the phospholipids aligned in the interior. The lipid bilayer theory explains the ob
`servation that lipid-soluble drugs tend to penetrate cell membranes more easily
`than polar molecules. However, the bilayer cell membrane structure does not ac-
`count for the diffusion of water, small-molecular—weight molecules such as urea,
`
`Page 6
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`
`374
`
`
`CHAPTER13. EHYSlQLQQlC l‘ACTQRS RELATED TO DRUG ABSORPTlON
`
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`O
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`Transcellular transport
`Paracellular transport
`
`Intestinal epithelial cell
`
`/
`Brush-border
`membrane
`
`\
`Bosolaleml
`membrane
`
` Na‘l
`Na*/Amino acid -
`
`
`' _- Amino acid -
`
`
`
`-.
`Na", CUB-Amino acid
`
` HVOligopeplide a
`
`
`Na*/D-Glucose
`
`D-Fruclose
`
`H"/I.aclic acid
`
`HVSCFA
`
`HC03'/
`
`Monocarboxylic acid
`m
`
`
`Nu*/Phosphate
`Na+/Bile acid
`
`H+/Nicoiinic acid
`
`HCOf/Nicofinic acid
`
`Amino acid
`Amino acid
`
`H+/
`Oligopeplide
`
`Hexose
`H+/
`Laclic acid
`
`NOV
`Phosphate
`
`
`
`OH_/Folic acid
`Choline
`
`
` P-Glycoprolein
`
`ATP
`
`N +
`NOW.
`° m
`
`Anliporter
`ADP
`
`pH = 5.5—6.8
`H = 7.0
`pH = 7.4
`[Na+] = 140 mM
`[Na" = 10-20 rnM
`[Na”] = 140 mM
`
`Folic acid
`
`K+
`
`Figure 13-l . Summary of intestinal epithelial transporters. Transporters shown by square and oval
`shapes demonstrate active and facilitated transporters, respectively. Names of cloned transporters are
`shown with square or oval shapes. In the case of active transporter, arrows in the same direction
`represent symport of substance and the driving force. Arrows going in the reverse direction mean
`the antiport.
`(From Tsuji and Tamai, 19%, with permission.)
`
`The fluid mosaic model, proposed by Singer and Nicolson (1972), explains the
`transcellular diffusion of polar molecules. According to this model, the cell mem-
`brane consists of globular proteins embedded in a dynamic fluid, lipid bilayer
`matrix (Fig. 13-2). These proteins provide a pathway for the selective transfer of
`certain polar molecules and charged ions through the lipid barrier. As shown in
`
`
`
`
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`Page 7
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`Page 7
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`

`

`PHYSIOLOGlC FACTORS RELATED TO DRUG ABSORPTION _C_HAPTER13.
`
`375
`
`Carbohydrate
`
`I
`
`.
`
`I' ”'SIy-‘loplusm
`
`Figure 13-2. Model of the plasma membrane including proteins and carbohydrates as well as lipids.
`integral proteins areembeddedIn the lipid bilayer, peripheral proteins are merely associated with the
`membrane surface. The carbohydrate consists of monosaccharides, or simple sugars strung together
`in chains attached to proteins (forming glycoproteins) or to lipids (forming glycolipids). The asymmetry
`of the membrane'lS manifested in several ways. Carbohydrates are always on the exterior surface and
`peripheral proteins are almost always on the cytoplasmic or inner surface. The two lipid monolayers
`include different proportions of the whims kinds of lipid molecule. Most important, each species of
`integral protein has a definite orientation which is the same for every molecule of that species.
`(From Lodish and Rothman 1979, with permission. l
`
`‘s
`
`Figure 13-2, u'ansmembrane proteins are interdispersed throughout the mem-
`brane. Two types of pores of about 10 nm and 50 to 70 nm weir.- inferled to be
`present in membranes based on capillary membrane transport studies (PIatt and
`Taylor, 1990). These small pores ptov1de a channel through which water, ions, and
`dissolved solutes such as urea may move across the membrane.
`
`When one side is higher in drug concentration, at any given time, the number of
`
`PASSAGE OF DRUGS ACROSS CELL MENIBRANES '
`
`PaSsive Diffusion
`
`Theoretically, a lipophilic drug may pass through the cell or go around it. If the
`drug has a low molecular weight and is lipophilic, the lipid cell membrane is not
`a barrier to drug diffusion and absorption. Passive diffitsion is the process by which
`molecules spontaneously diffuse from a region of higher concentration to a region
`of lower Concentration. This process is passive beCause no external energy is ex—
`pended. In Figure “13-3, drug molecules move forward and back across a mem-
`brane. If the two sides have the same drug» concentration, forward-moving drug mol-
`ecules are balanced by molecules moving back, resulting in no net transfer of drug.
`
`Page 8
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`376
`
`CHAPTERIS. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION
`
`of molecules.
`diffusion
`Passive
`13-3.
`Figure
`Molecules in solution diffuse randomly in all directions.
`As molecules diffuse from left to right and vice versa
`(small
`arrows),
`a net diffusion from the high-
`concentration side to the low—concentration side
`results. This results in a net flux (J) to the right side.
`Flux is measured in mass per unit area leg, mg/cmzl.
`
`Membrane
`
`
`
`High
`concenlrolion
`
`“UK“
`lOW .
`concen'mh‘m
`
`forward-moving drug molecules will be higher than the number of backward-moving
`molecules; the net result will be a transfer of molecules to the alternate side, as in-
`
`dicated in the figure by the big arrow. The rate of transfer is called flux, and is rep-
`resented by a vector to show its direction in space. The tendency of molecules to
`move in all directions is natural, because molecules possess kinetic energy and con-
`stantly collide with one another in space. Only left and right molecule movements
`are shown in Figure 13—3, because movement of molecules in other directions will
`not result in concentration changes because of the limitation of the container wall.
`Passive diffusion is the major absorption process for most drugs. The driving
`force for passive diffusion is higher drug concentrations on the mucosal side com-
`pared to the blood. According to Firk’s law of diflusion, drug molecules diffuse from
`a region of high drug concentration to a region of low drug concentratiOn.
`
`d
`
`DAK
`
`(1:2: —(ch- Cp)
`
`(13-1)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`where dQ/dt—— rate of diffusion, D—— diffusion coefficient K—— lipid water parli-
`tion coefficient of drug1n the biologic membrane that controls drug permeation,
`A—— surface area of membrane; h: membrane thickness, and CGI— CF: difference
`between the concentrations of drug1n the gastrointestinal tract and in the plasma.
`Because the drug distributes rapidly into a large volume after enteringthe blood,
`the concentration of drug1n the blood initially will be quite low with respect to the
`concentration at the site of drug absorption. For example, a drugis usually given
`in milligram doses, whereas plasma concentrations are often1n the microgram-
`per—-milliliter or nanogram—per—-milliliter range. If the drug is given orally, then
`CGI>> CP and a large concentration gradient is maintained,
`thus driving drug
`molecules into the plasma from the gastrointestinal tract.
`Given Fick’ law of diffusion, several other factors can be seen to influence the
`rate of passive diffusion of drugs. For example, the degree of lipid solubility of
`the drug influences the rate of drug absorption. The partition coefficient, K rep—
`resents the lipid—water partitioning of a drug across the hypotheticallrnemb‘rane in
`the mucosa. Drugs that are more lipid soluble have a larger. value of K’The sur-
`face area, A, of the membrane also influences the rate of absorption; Drugs may
`be absorbed from most areas of the gastrointestinal tract. However, the duodenal
`area of the small intestine shows the most rapid drug absorption, due, to such
`anatomic features as villi and microvilli, which provide a large surface area. These
`villi are less abundantIn other areas of the gastrointestinal tract.
`.
`The thickness of the hypothetical model membrane, h, is a constant for any par—
`ticular absorption site Drugs usually diffuse very rapidly through capillary plasma
`membranes in the vascular compartments, in contrast to diffusion through plasma
`
`membranes of capillaries in the brain. In the brain, the capillaries are densely lined
`
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`Page 9
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`Page 9
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`
`PHYSIOLOGIC FAgTORS RELATED TO DRUG ABSORPTION CHAPTER 13.
`
`377
`
`with glial cells, so a drug diffuses slowly into the brain as if a thick lipid membrane
`existed. The term blood—brain bam‘er is used to describe the poor diffusion of Water-
`soluble molecules across capillary plasma membranes into the-brain. However, in cer-
`tain disease states such as meningitis these membranes may be disrupted or become
`more permeable to drug diffusion.
`The diffusion coefficient, D, is a constant for each drug and is defined as the
`amount of a drug that diffuses across a membrane of a given unit area per unit
`time when the concentration gradient is unity. The dimensions of D are area per
`unit time—for example, cmz/sec.
`Because D, A, K and h are constants under usual conditions for absorption, a
`combined constant P or permeability coefficient may be defined.
`
`_ DAK
`h
`
`P
`
`.
`
`(13.2)
`
`Furthermore, in‘Equation 13.1 the drug concentration in the plasma, Cp’ is ex—
`tremely'small compared tothe drug'concentration in the gastrointestinal tract, car-
`If Cp is negligible and, P is Substituted into Equation 13.1 , the following relation-
`ship for Fick’s law is obtained:
`V
`
`a!
`
`7:2 = Ham)
`
`(13.3)
`
`Equation 13.3 is an expression for a first-order process. In practice, the ex-
`travascular absorption of most drugs tends to be a first-order absorption process.
`Moreover, because of the large concentration gradient betweEn CGI and Cp, the rate
`of drug absorption is usually more rapid than the rate of drug elimination.
`Many drugs have both lipophilic and hydrophilic chemical substituents. Those
`drugs that are more lipid soluble tend to traverse cell membranes more easily than
`less lipid—soluble or more water-soluble molecules. For drugs that act as weak elec-
`trolytes, such as weak aé‘ids and bases, the extent of ionization influences the rate
`of drug transport. The ioniied species of‘ theidrug contains a charge and is more
`water soluble than the nOnionized species of the drug,which is more lipid soluble.
`.1116 extent ofionization of a" weak (electrolytewill~ depend on both the pK, of the
`[drag and the ‘pH at me medium in which the drug’is (dissolved. Henderson and
`Hasselbqlch used‘the following expressions pertaining to weak acids and weak bases
`to‘ describe the relationship between pKa and pH:
`.be Weak acids,
`‘
`‘4‘“. v: 3'
`x
`,‘A‘
`
`)
`
`
`
`
`
`
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`
`
`For Weak bases,
`
`
`
`RNH
` [base]
`
`=_ _[2] = 10(PH—PK.)
`(13.5)
`
`"
`_ Ratio =
`[RNHg]
`
`
`
`
`
`
`
`
`[salt]
`
`With Equations 13.4 and 13.5, the proportion of free acid or free base existing as
`the nonionized species may be determined at any given pH, assuming the pKa for
`
`Page 10
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`Page 10
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`378
`
`CHAPTER 13.
`
`PHYS_lOL_OGIC FACTORS RELATED TO DRUG ABSORPTION
`
`the drug is known. For example, at a plasma pH of 7.4, salicylic acid (pKa = 3.0)
`exists mostly in its ionized or water-soluble form, as shown below:
`
`Ratio =
`
`= 1004-30)
`
`
`[salt]
`.
`[amd]
`
`[salt]— 74
`0g [acid] _ i
`
`lt
`[sa] = 251 X 104
`[aetd]
`
`1
`
`30 1 44
`' _ .
`
`In a simple system, the total drug concentration on either side of a membrane
`should be the same at equilibrium, assuming Fick’s law of diffusion is the only
`distribution factor involved. For diffusible drugs, such as nonelectrolyte drugs or
`drugs that do not ionize, the drug concentrations on either side of the membrane
`are the same at equilibrium. However, for electrolyte drugs or drugs that ionize,
`the total drug concentrations on either side of the membrane are not equal at equi—
`librium if the pH of the medium differs on respective sides of the membrane. For
`example, consider the concentration of salicylic acid (pig = 3.0) in the stomach
`(pH 1.2) as opposed to its concentration in the plasma (pH 7.4)
`(Fig. 13-4).
`According to the Henderson—Hasselbalch equation (Eq. 13.4) for weak acids, at
`pH 7.4 and at pH 1.2, salicylic acid exists in the ratios that follow.
`In the plasma, at pH 7.4:
`
`RaLi _&gg)__251><104
`°
`(RCOOH)
`'
`
`In gastric juice, at pH 1.2:
`
`(RCOO‘)
`R u = —— = 1002—“) = 1.58 x 10—2
`(RCOOH)
`a O
`
`The total drug concentration on either side of the membrane is determined as
`shown in Table 13.2.
`Thus, the pH affects distribution of salicylic acid (RCOOH) and its salt (RCOO‘)
`across cell membranes. It is assumed that the acid, RCOOH, is freely permeable
`and the salt, RCOO‘, is riot permeable across the cell membrane. In this example
`the total concentration of salicylic acid at equilibrium is approximately 25,000 times
`greater in the plasma than in the stomach (Table 13.2). These calculations can
`also be applied to weak bases, using Equation 13.5.
`
`Figure 13-4. Model for the distribution of an orally
`administered weak electrolyte drug such as salicylic
`acid.
`
`Gastric iuice (pH 1.2)
`
`Plasma (pH 7.4)
`
`RCOOH :5: R COOH
`1L
`,
`E
`1)
`R COO' “+30,
`i
`R COO'+H30*
`
`
`
`Page 11
`
`Page 11
`
`

`

`
`PHYSIOLOGIC FACIORS RELATED TO DRUG ABSORPTION CHAPTER 13.
`
`TABLE 13.2 Relative Concentrations of Salicylic Acid as Affected by pH
`
`GASTRIC JUICE
`,
`.
`DRUG“;'a
`
`RCOOH
`RCOO—
`Total drug concentration
`
`metabolites (such as 5-fluorouracil) are absorbed from the, gastrointestinal tract by
`
`According to the pH-partition hypothesis, if the pH on one side of a cell membrane
`differs from the pH on the other side of the membrane, then (1) the dmg (weak acid
`or base) will ionize to diiferent degrees on respective sides of the membrane; (2) the
`total drug concentrations (ionized plus nonionized drug) on either side of the mem-
`brane will be unequal; and (3) the compartment in which the drug is more highly
`ionized will contain the greater total drug concentration. For these reasons, a weak
`acid (such as salicylic acid) will be rapidly absorbed from the stomach (pH 1.2),
`whereas a weak base (such as quinidine) will be poorly absorbed from the stomach.
`Another factor that can influence drug concentrations on either side of a mem—
`brane is a particular aflinity of the drug for a tissue component, which prevents the
`drug from moving freely back across the cell membrane. For example, a drug such
`as dicumarol binds to plasma protein, and digoxin binds to tissue protein. In each
`case, the protein——bound drug does not move freely across the cell membrane. Drugs
`such as chlordane are very lipid soluble and will partition into adipose (fat) tissue
`In addition, a drug such as tetracycline might form a complex with calcium1n the
`bones and teeth. Finally, a drug may concentrate in a tissue due to a specific up—
`takeor active transport process. Such processes have been demonstrated for iodide
`in thyroid tissue, potassium in the intracellular water, and certain catecholamines
`into adrenergic storage sites. Such drugs may have a higher total drug concentra-
`tion on the side where binding occurs, yet the free drug concentration that dif—
`fuses across cell membranes will be the same on both sides of the membrane.
`Instead of diffusing into the cell, drugs can also diffuse into the spaces around
`the cell as an absorption mechanism. In paracellular drug absorption, drug molecules
`smaller than 500 MW diffuse into the tight junctions, or spaces between intestinal
`epithelial cells.
`
`Carrier-Mediated Transport
`
`Theoretically, a lipophilic drug may pass through the cell or go around it. If the
`drug has a low molecular weight and is lipophilic, the lipid cell membrane is not
`a barrier to drug diffusion and absorption. In the intestine, drugs and other mol—
`ecules can go through the intestinal epithelial cells by either diffusion or a carrier—
`mediated mechanism. Numerous specialized carrier—mediated transport systems
`are present in the body, especially in the intestine for the absorption of ions and
`nutrients required by the body.
`
`Active Transport
`Active transport is a carrier—mediated transmembrane process that plays an impor-
`tant role in the gastrointestinal absorption and in renal and biliary secretion of many
`drugs and metabolites. A few lipid—insoluble drugs that resemble natural physiologic
`
`Page 12
`
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`
`

`

`380
`
`EHAPTER 13." l’_l-lY_SlOLOGlC FACTORS RELATED TO DRUG ABSOlilelON
`
`GI lumen
`
`lnteslinal epithelial cell
`
`Blood
`
`I lI
`
`Drug
`
`I I
`
`II
`
`Carrier
`
`Drug
`
`carrier
`
`
`complex
`
`
`Carrier
`Drug fi—F +
`Drug
`
`
`Figure 13-5. Hypothetical carrier—mediated transport process.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`this process. Active transport is characterized by the transport of drug against a con—
`centralion gradient—that is, from regions of low drug concentrations to regions of
`high concentrations. Therefore, this is an energy-consuming system. In addition, ac-
`tive transport is a specialized process requiring a carrier that binds the drug to form
`a carrier—drug complex that shuttles the drug across the membrane and then dis—
`sociates the drug on the other side of the membrane (Fig. 13—5).
`The carrier molecule may be highly selective for the drug molecule. If the drug
`structurally resembles a natural substrate that is actively transported, then it is likely
`to be actively transported by the same carrier mechanism. Therefore, drugs of sim—
`ilar structure may compete for sites of adsorption on the carrier. Furthermore, be-
`cause only a fixed number of carrier molecules are available, all the binding sites
`on the carrier may become saturated if the drug concentration gets very high. A
`comparison between the rate of drug absorption and the concentration of drug at
`the absorption site is shown in Figure 13-6. Notice that for a drug absorbed by
`passive diffusion, the rate of absorption increases in a linear relationship to drug
`concentration. In contrast, when a drug is absorbed by a carrier-mediated process,
`the rate of drug absorption increases with drug concentration until the carrier
`molecules are completely saturated. At higher drug concentrations, the rate of drug
`absorption remains constant, or zero order.
`
`Facilitated Diffiuion
`Facilitated diffusion is also a carrier-mediated transport system, differing from
`active transport in that the drug moves along a concentration gradient (ie, moves
`from a region of high drug concentration to a region of low drug concentration).
`Therefore, this system does not require energy input. However, because this system
`is carrier mediated, it is saturable and structurally selective for the drug and shows
`competition kinetics for drugs of similar structure. In terms of drug absorption,
`facilitated diffusion seems to play a very minor role.
`'
`
`the rates of drug
`Figure 13-6. Comparison of
`absorption of a drug absorbed by passive diffusion
`
`(line A) and a drug absorbed by a carrier-mediated
`system (line B).
`Concentration of drug
`
`
`
`
`absorption
`
`Rateclclmg
`
`
`Page 13
`
`Page 13
`
`

`

`PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION CHAPTERIIE1
`
`381
`
`TABLE 13.3 Intestine Transporters and Examples of Drugs Transported
`
` TRANSPORTER EXAMPLES
`
`
`Amino acid transporter
`
`Oligopeptide transporter
`
`Phosphate transporter
`Bile acid transporter
`Glucose transporter
`P—glycoprotein effiux
`
`Gabapentin
`Methyldopa
`L—dopa
`Cefadroxil
`Cefixlme
`Cephalexrn
`Lisinopril
`Fostomycin
`S3744
`pNitrophenyl—fi-Dglucopyranoside
`Etoposide
`Cyclosporin A
`Benzoic acid
`Salicylic acid
`Monocarboxylic acid
`Pravastatin
`transporter
`
`
`DCycloserine
`Baclofen
`
`Cephradine
`Ceftibuten
`Captopril
`Thrombin inhibitor
`Foscarnet
`
`Wnblastine
`
`Adapted from Tsuji and Tamai (19%|.
`
`Carrier-Mediated Intestinal Transport
`Various carrier-mediated systems (transporters) are present at the intestinal brush
`border and basolateral membrane for the absorption of specific ions and nutrients
`essential for the body (Tsuji and Tamal, 1996). Many drugs are absorbed by these
`carriers because of the structural similarity to natural substrates (Table 13.3). A
`transmembranc protein, P-glycoprotein (ng), has been identified in the intes-
`tine. ng appears to reduce apparent intestinal epithelial cell permeability from
`lumen to blood for various lipophilic or cytotoxic drugs and is discussed in more
`detail below. Other transporters are also present in the intestines (Tsuji and Tamai,
`1996). For example, many oral cephalospoisins are absorbed through the amino
`acid transporter. Cefazolin, a parenteral-only cephalo‘sporin, is not available orally
`because it cannot be absorbed to a significant degree through this mechanism.
`
`Vesicular Transport
`
`Vesicular transport is the process of engulfing particles or dissolved materials by
`the cell. Pinocytosis and phagocytosis are forms of vesicular transport that differ by
`the type of material ingested. Pinocytosis refers to the engulfment of small solutes
`or fluid, whereas phagocytosis refers to the cngulfment of larger particles or macro-
`molecules, generally by macrophages. Endocytasis and exocytosis are the processes of
`moving specific macromolecules into and out of a cell, respectively.
`During pinocytosis or phagocytosis, the cell membrane invaginates to surround
`the material and then engulfs the material, incorporating it into the cell (Fig. 13-7).
`Subsequently, the cell membrane containing the material forms a vesicle or vacuole
`within the cell. Vesicular transport is the proposed process for the absorption of orally
`administered Sabin polio vaccine and various large proteins.
`An example of exocytosis is the transport of a protein such as insulin from insulin—
`producing cells of the pancreas into the extracellular space. The insulin molecules
`are first packaged into intracellular vesicles, which then fuse with the plasma
`membrane to release the insulin