Chapter 1: Pharmacokinetics

Question 1

Routes of drug administration

Enteral

Answer 1

Parenteral
The parenteral route introduces drugs directly into the systemic cir-
culation. Parenteral administration is used for drugs that are poorly absorbed from the GI tract (for example, heparin) or unstable in
the GI tract (for example, insulin). Parenteral administration is also
used if a patient is unable to take oral medications (unconscious
patients) and in circumstances that require a rapid onset of action.
In addition, parenteral routes have the highest bioavailability and
are not subject to first-pass metabolism or the harsh GI environ-
ment. Parenteral administration provides the most control over the
actual dose of drug delivered to the body. However, these routes
of administration are irreversible and may cause pain, fear, local
tissue damage, and infections. The three major parenteral routes
are intravascular (intravenous or intra-arterial), intramuscular, and
subcutaneous (Figure 1.3).
1. Intravenous (IV): IV injection is the most common parenteral
route. It is useful for drugs that are not absorbed orally, such as
the neuromuscular blocker rocuronium. IV delivery permits a
rapid effect and a maximum degree of control over the amount
of drug delivered. When injected as a bolus, the full amount of
drug is delivered to the systemic circulation almost immediately. If
administered as an IV infusion, the drug is infused over a longer
period of time, resulting in lower peak plasma concentrations and
an increased duration of circulating drug levels. IV administration
is advantageous for drugs that cause irritation when administered
via other routes, because the substance is rapidly diluted by the
blood. Unlike drugs given orally, those that are injected cannot be
recalled by strategies such as binding to activated charcoal. IV
injection may inadvertently introduce infections through contami-
nation at the site of injection. It may also precipitate blood con-
stituents, induce hemolysis, or cause other adverse reactions if
the medication is delivered too rapidly and high concentrations are
reached too quickly. Therefore, patients must be carefully moni-
tored for drug reactions, and the rate of infusion must be carefully
controlled.
2. Intramuscular (IM): Drugs administered IM can be in aque-
ous solutions, which are absorbed rapidly, or in specialized
depot preparations, which are absorbed slowly. Depot prepara-
tions often consist of a suspension of the drug in a nonaqueous
vehicle such as polyethylene glycol. As the vehicle diffuses out
of the muscle, the drug precipitates at the site of injection. The
drug then dissolves slowly, providing a sustained dose over an
extended period of time. Examples of sustained-release drugs
are haloperidol (see Chapter 11) and depot medroxyprogester-
one (see Chapter 26).
3. Subcutaneous (SC): Like IM injection, SC injection provides
absorption via simple diffusion and is slower than the IV route. SC
injection minimizes the risks of hemolysis or thrombosis associ-
ated with IV injection and may provide constant, slow, and sus-
tained effects. This route should not be used with drugs that cause
tissue irritation, because severe pain and necrosis may occur.
Drugs commonly administered via the subcutaneous route include
insulin and heparin.

Question 2

Others

Answer 2

Other
1. Oral inhalation: Inhalation routes, both oral and nasal (see
discussion of nasal inhalation), provide rapid delivery of a drug
across the large surface area of the mucous membranes of the
respiratory tract and pulmonary epithelium. Drug effects are
almost as rapid as those with IV bolus. Drugs that are gases (for
example, some anesthetics) and those that can be dispersed in
an aerosol are administered via inhalation. This route is effective
and convenient for patients with respiratory disorders (such as
asthma or chronic obstructive pulmonary disease), because the
drug is delivered directly to the site of action, thereby minimizing
systemic side effects. Examples of drugs administered via inha-
lation include bronchodilators, such as albuterol, and corticoste-
roids, such as fluticasone.
2. Nasal inhalation: This route involves administration of drugs
directly into the nose. Examples of agents include nasal decon-
gestants, such as oxymetazoline, and corticosteroids, such as
mometasone furoate. Desmopressin is administered intranasally
in the treatment of diabetes insipidus.
3. Intrathecal/intraventricular: The blood–brain barrier typically
delays or prevents the absorption of drugs into the central nervous
system (CNS). When local, rapid effects are needed, it is neces-
sary to introduce drugs directly into the cerebrospinal fluid. For
example, intrathecal amphotericin B is used in treating cryptococ-
cal meningitis (see Chapter 42).
4. Topical: Topical application is used when a local effect of the drug
is desired. For example, clotrimazole is a cream applied directly to
the skin for the treatment of fungal infections.
5. Transdermal: This route of administration achieves systemic
effects by application of drugs to the skin, usually via a transder-
mal patch (Figure 1.4). The rate of absorption can vary markedly,
depending on the physical characteristics of the skin at the site
of application, as well as the lipid solubility of the drug. This route
is most often used for the sustained delivery of drugs, such as
the antianginal drug nitroglycerin, the antiemetic scopolamine, and
nicotine transdermal patches, which are used to facilitate smoking
cessation.
6. Rectal: Because 50% of the drainage of the rectal region
bypasses the portal circulation, the biotransformation of drugs by
the liver is minimized with rectal administration. The rectal route
has the additional advantage of preventing destruction of the drug
in the GI environment. This route is also useful if the drug induces
vomiting when given orally, if the patient is already vomiting, or if
the patient is unconscious. [Note: The rectal route is commonly
used to administer antiemetic agents.] Rectal absorption is often
erratic and incomplete, and many drugs irritate the rectal mucosa.
Figure 1.5 summarizes the characteristics of the common routes
of administration.

Question 3

ABSORPTION OF DRUGS

Passive diffusion

Answer 3

Mechanisms of absorption of drugs from the GI tract
Depending on their chemical properties, drugs may be absorbed from
the GI tract by passive diffusion, facilitated diffusion, active transport,
or endocytosis (Figure 1.6).
1. Passive diffusion: The driving force for passive absorption of
a drug is the concentration gradient across a membrane sepa-
rating two body compartments. In other words, the drug moves
from a region of high concentration to one of lower concentra-
tion. Passive diffusion does not involve a carrier, is not saturable,
and shows a low structural specificity. The vast majority of drugs
are absorbed by this mechanism. Water-soluble drugs pene-
trate the cell membrane through aqueous channels or pores,
whereas lipid-soluble drugs readily move across most biologic
membranes due to their solubility in the membrane lipid bilayers.

Question 4

Facilitated diffusion

Answer 4

Facilitated diffusion: Other agents can enter the cell through spe-
cialized transmembrane carrier proteins that facilitate the passage
of large molecules. These carrier proteins undergo conformational
changes, allowing the passage of drugs or endogenous molecules
into the interior of cells and moving them from an area of high con-
centration to an area of low concentration. This process is known
as facilitated diffusion. It does not require energy, can be saturated,
and may be inhibited by compounds that compete for the carrier.

Question 5

Active transport

Answer 5

Active transport: This mode of drug entry also involves spe-
cific carrier proteins that span the membrane. A few drugs that
closely resemble the structure of naturally occurring metabolites
are actively transported across cell membranes using specific
carrier proteins. Energy-dependent active transport is driven by
the hydrolysis of adenosine triphosphate. It is capable of moving
drugs against a concentration gradient, from a region of low drug
concentration to one of higher drug concentration. The process is
saturable. Active transport systems are selective and may be com-
petitively inhibited by other cotransported substances.

Question 6

Endocytosis and exocytosis

Answer 6

Endocytosis and exocytosis: This type of absorption is used
to transport drugs of exceptionally large size across the cell
membrane. Endocytosis involves engulfment of a drug by the cell
membrane and transport into the cell by pinching off the drug-
filled vesicle. Exocytosis is the reverse of endocytosis. Many
cells use exocytosis to secrete substances out of the cell through
a similar process of vesicle formation. Vitamin B12 is transported
across the gut wall by endocytosis, whereas certain neurotrans-
mitters (for example, norepinephrine) are stored in intracellular
vesicles in the nerve terminal and released by exocytosis

Question 7

Factors influencing absorption

Effect of pH

Answer 7

1. Effect of pH on drug absorption: Most drugs are either weak
   acids or weak bases. Acidic drugs (HA) release a proton (H+),
   causing a charged anion (A−) to form:
   HA H A + − +
   Weak bases (BH+) can also release an H+. However, the proton-
   ated form of basic drugs is usually charged, and loss of a proton
   produces the uncharged base (B):
   BH B H + + +
   A drug passes through membranes more readily if it is uncharged
   (Figure 1.7). Thus, for a weak acid, the uncharged, proton-
   ated HA can permeate through membranes, and A− cannot. For
   a weak base, the uncharged form B penetrates through the cell
   membrane, but the protonated form BH+ does not. Therefore, the
   effective concentration of the permeable form of each drug at its
   absorption site is determined by the relative concentrations of the
   charged and uncharged forms. The ratio between the two forms
   is, in turn, determined by the pH at the site of absorption and by
   the strength of the weak acid or base, which is represented by
   the ionization constant, pKa
   (Figure 1.8). [Note: The pKa
   is a mea-
   sure of the strength of the interaction of a compound with a proton.
   The lower the pKa
   of a drug, the more acidic it is. Conversely, the
   higher the pKa
   , the more basic is the drug.] Distribution equilibrium
   is achieved when the permeable form of a drug achieves an equal
   concentration in all body water spaces.

Question 8

2. Blood flow to the absorption site

Answer 8

Blood flow to the absorption site: The intestines receive much
more blood flow than the stomach, so absorption from the intestine
is favored over the stomach. [Note: Shock severely reduces blood
flow to cutaneous tissues, thereby minimizing absorption from SC
administration.]

Question 9

Total surface area available for absorption

Answer 9

Total surface area available for absorption: With a surface rich
in brush borders containing microvilli, the intestine has a surface
area about 1000-fold that of the stomach, making absorption of the
drug across the intestine more efficient

Question 10

Contact time at the absorption surface

Answer 10

4. Contact time at the absorption surface: If a drug moves
   through the GI tract very quickly, as can happen with severe diar-
   rhea, it is not well absorbed. Conversely, anything that delays the
   transport of the drug from the stomach to the intestine delays
   the rate of absorption of the drug. [Note: The presence of food
   in the stomach both dilutes the drug and slows gastric emptying.
   Therefore, a drug taken with a meal is generally absorbed more
   slowly.]

Question 11

Expression of p-glycoprotein

Answer 11

5. Expression of P-glycoprotein: P-glycoprotein is a transmem-
   brane transporter protein responsible for transporting various
   molecules, including drugs, across cell membranes (Figure 1.9).
   It is expressed in tissues throughout the body, including the
   liver, kidneys, placenta, intestines, and brain capillaries, and is
   involved in transportation of drugs from tissues to blood. That is, it
   “pumps” drugs out of the cells. Thus, in areas of high expression,
   P-glycoprotein reduces drug absorption. In addition to transport-
   ing many drugs out of cells, it is also associated with multidrug
   resistance.

Question 12

Bioavailability

Answer 12

Bioavailability is the rate and extent to which an administered drug
reaches the systemic circulation. For example, if 100 mg of a drug
is administered orally and 70 mg is absorbed unchanged, the bio-
availability is 0.7 or 70%. Determining bioavailability is important for
calculating drug dosages for nonintravenous routes of administration.

1. Determination of bioavailability: Bioavailability is determined
   by comparing plasma levels of a drug after a particular route
   of administration (for example, oral administration) with levels
   achieved by IV administration. After IV administration, 100% of the
   drug rapidly enters the circulation. When the drug is given orally,
   only part of the administered dose appears in the plasma. By
   plotting plasma concentrations of the drug versus time, the area
   under the curve (AUC) can be measured. The total AUC reflects
   the extent of absorption of the drug. Bioavailability of a drug given
   orally is the ratio of the AUC following oral administration to the
   AUC following IV administration (assuming IV and oral doses are
   equivalent; Figure 1.10).

Question 13

Factors that influence bioavailability:

In contrast to IV admin-
istration, which confers 100% bioavailability, orally administered
drugs often undergo first-pass metabolism. This biotransformation,
in addition to the chemical and physical characteristics of the drug,
determines the rate and extent to which the agent reaches the
systemic circulation.

Answer 13

a. First-pass hepatic metabolism: When a drug is absorbed
from the GI tract, it enters the portal circulation before enter-
ing the systemic circulation (Figure 1.11). If the drug is rap-
idly metabolized in the liver or gut wall during this initial
passage, the amount of unchanged drug entering the sys-
temic circulation is decreased. This is referred to as first-pass metabolism. [Note: First-pass metabolism by the intestine
or liver limits the efficacy of many oral medications. For
example, more than 90% of nitroglycerin is cleared during
first-pass metabolism. Hence, it is primarily administered
via the sublingual or transdermal route.] Drugs with high
first-pass metabolism should be given in doses sufficient to
ensure that enough active drug reaches the desired site of
action.

Question 14

Solubility of the drug

Answer 14

Solubility of the drug: Very hydrophilic drugs are poorly
absorbed because of their inability to cross lipid-rich cell mem-
branes. Paradoxically, drugs that are extremely lipophilic are
also poorly absorbed, because they are totally insoluble in
aqueous body fluids and, therefore, cannot gain access to the
surface of cells. For a drug to be readily absorbed, it must be
largely lipophilic, yet have some solubility in aqueous solutions.
This is one reason why many drugs are either weak acids or
weak bases.

Question 15

Chemical instability

Answer 15

Chemical instability: Some drugs, such as penicillin G, are
unstable in the pH of the gastric contents. Others, such as
insulin, are destroyed in the GI tract by degradative enzymes.

Question 16

Nature of drug formulation

Answer 16

Nature of the drug formulation: Drug absorption may be
altered by factors unrelated to the chemistry of the drug. For
example, particle size, salt form, crystal polymorphism, enteric
coatings, and the presence of excipients (such as binders and
dispersing agents) can influence the ease of dissolution and,
therefore, alter the rate of absorption.

Question 17

Bioequivalence

Answer 17

Bioequivalence
Two drug formulations are bioequivalent if they show comparable bio-
availability and similar times to achieve peak blood concentrations

Question 18

Therapeutic equivalent

Answer 18

Therapeutic equivalence
Two drug formulations are therapeutically equivalent if they are
pharmaceutically equivalent (that is, they have the same dosage
form, contain the same active ingredient, and use the same route of
administration) with similar clinical and safety profiles. [Note: Clinical
effectiveness often depends on both the maximum serum drug con-
centration and the time required (after administration) to reach peak
concentration. Therefore, two drugs that are bioequivalent may not
be therapeutically equivalent.]

Question 19

DRUG DISTRIBUTION

Blood flow

Answer 19

A. Blood flow
The rate of blood flow to the tissue capillaries varies widely. For
instance, blood flow to the “vessel-rich organs” (brain, liver, and kid-
ney) is greater than that to the skeletal muscles. Adipose tissue, skin,
and viscera have still lower rates of blood flow. Variation in blood
flow partly explains the short duration of hypnosis produced by an
IV bolus of propofol (see Chapter 13). High blood flow, together with
high lipophilicity of propofol, permits rapid distribution into the CNS
and produces anesthesia. A subsequent slower distribution to skel-
etal muscle and adipose tissue lowers the plasma concentration so
that the drug diffuses out of the CNS, down the concentration gradi-
ent, and consciousness is regained.

Question 20

Capillary permeability

Answer 20

Capillary permeability
Capillary permeability is determined by capillary structure and by
the chemical nature of the drug. Capillary structure varies in terms
of the fraction of the basement membrane exposed by slit junc-
tions between endothelial cells. In the liver and spleen, a signifi-
cant portion of the basement membrane is exposed due to large,
discontinuous capillaries through which large plasma proteins can
pass (Figure 1.13A). In the brain, the capillary structure is con-
tinuous, and there are no slit junctions (Figure 1.13B). To enter
the brain, drugs must pass through the endothelial cells of the
CNS capillaries or be actively transported. For example, a specific
transporter carries levodopa into the brain. By contrast, lipid-solu-
ble drugs readily penetrate the CNS because they dissolve in the
endothelial cell membrane. Ionized or polar drugs generally fail to
enter the CNS because they cannot pass through the endothelial
cells that have no slit junctions (Figure 1.13C). These closely jux-
taposed cells form tight junctions that constitute the blood–brain
barrier.

Question 21

Binding of drugs to plasma proteins and tissues

Answer 21

Binding to plasma proteins: Reversible binding to plasma
proteins sequesters drugs in a nondiffusible form and slows
their transfer out of the vascular compartment. Albumin is the
major drug-binding protein and may act as a drug reservoir (as
the concentration of free drug decreases due to elimination, the
bound drug dissociates from the protein). This maintains the free-
drug concentration as a constant fraction of the total drug in the
plasma

Question 22

Binding to tissue protein

Answer 22

Binding to tissue proteins: Many drugs accumulate in tissues,
leading to higher concentrations in tissues than in the extracel-
lular fluid and blood. Drugs may accumulate as a result of binding to lipids, proteins, or nucleic acids. Drugs may also be actively
transported into tissues. Tissue reservoirs may serve as a major
source of the drug and prolong its actions or cause local drug
toxicity. (For example, acrolein, the metabolite of cyclophospha-
mide, can cause hemorrhagic cystitis because it accumulates in
the bladder.)

Question 23

Lipophilicity

Answer 23

The chemical nature of a drug strongly influences its ability to cross
cell membranes. Lipophilic drugs readily move across most biologic
membranes. These drugs dissolve in the lipid membranes and pen-
etrate the entire cell surface. The major factor influencing the distribu-
tion of lipophilic drugs is blood flow to the area. In contrast, hydrophilic
drugs do not readily penetrate cell membranes and must pass through
slit junctions.

Question 24

Volume of distribution

Answer 24

Volume of distribution
The apparent volume of distribution, Vd
, is defined as the fluid volume
that is required to contain the entire drug in the body at the same
concentration measured in the plasma. It is calculated by dividing the
dose that ultimately gets into the systemic circulation by the plasma
concentration at time zero (C0
).
V
C d = Amount of drug in the body
0
Although Vd
has no physiologic or physical basis, it can be useful to
compare the distribution of a drug with the volumes of the water com-
partments in the body.
1. Distribution into the water compartments in the body: Once a
drug enters the body, it has the potential to distribute into any one
of the three functionally distinct compartments of body water or to
become sequestered in a cellular site.
a. Plasma compartment: If a drug has a high molecular weight
or is extensively protein bound, it is too large to pass through the
slit junctions of the capillaries and, thus, is effectively trapped
within the plasma (vascular) compartment. As a result, it has a
low Vd
that approximates the plasma volume or about 4 L in a
70-kg individual. Heparin (see Chapter 22) shows this type of
distribution.
b. Extracellular fluid: If a drug has a low molecular weight but
is hydrophilic, it can pass through the endothelial slit junctions
of the capillaries into the interstitial fluid. However, hydrophilic
drugs cannot move across the lipid membranes of cells to
enter the intracellular fluid. Therefore, these drugs distribute
into a volume that is the sum of the plasma volume and the
interstitial fluid, which together constitute the extracellular
fluid (about 20% of body weight or 14 L in a 70-kg individual).
Aminoglycoside antibiotics (see Chapter 39) show this type of
distribution.

c. Total body water: If a drug has a low molecular weight and
is lipophilic, it can move into the interstitium through the slit
junctions and also pass through the cell membranes into the
intracellular fluid. These drugs distribute into a volume of about
60% of body weight or about 42 L in a 70-kg individual. Ethanol
exhibits this apparent Vd
.
2. Apparent volume of distribution: A drug rarely associates
exclusively with only one of the water compartments of the body.
Instead, the vast majority of drugs distribute into several compart-
ments, often avidly binding cellular components, such as lipids
(abundant in adipocytes and cell membranes), proteins (abundant
in plasma and cells), and nucleic acids (abundant in cell nuclei).
Therefore, the volume into which drugs distribute is called the
apparent volume of distribution (Vd
). Vd
is a useful pharmacokinetic
parameter for calculating the loading dose of a drug.
3. Determination of Vd: The fact that drug clearance is usually a
first-order process allows calculation of Vd
. First order means that
a constant fraction of the drug is eliminated per unit of time. This
process can be most easily analyzed by plotting the log of the
plasma drug concentration (Cp
) versus time (Figure 1.14). The
concentration of drug in the plasma can be extrapolated back to
time zero (the time of IV bolus) on the Y axis to determine C0
,
which is the concentration of drug that would have been achieved
if the distribution phase had occurred instantly. This allows calcu-
lation of Vd
as
V Dose
C d =
0
For example, if 10 mg of drug is injected into a patient and the plasma
concentration is extrapolated back to time zero, and C0 = 1 mg/L
(from the graph in Figure 1.14B), then Vd = 10 mg/1 mg/L = 10 L.
4. Effect of Vd on drug half-life: Vd
has an important influence on
the half-life of a drug, because drug elimination depends on the
amount of drug delivered to the liver or kidney (or other organs
where metabolism occurs) per unit of time. Delivery of drug to the
organs of elimination depends not only on blood flow but also on
the fraction of the drug in the plasma. If a drug has a large Vd
,
most of the drug is in the extraplasmic space and is unavailable to
the excretory organs. Therefore, any factor that increases Vd
can
increase the half-life and extend the duration of action of the drug.
[Note: An exceptionally large Vd
indicates considerable sequestra-
tion of the drug in some tissues or compartments.]

Question 25

DRUG CLEARANCE THROUGH METABOLISM

Kinetics of metabolism

Answer 25

A. Kinetics of metabolism
1. First-order kinetics: The metabolic transformation of drugs is
catalyzed by enzymes, and most of the reactions obey Michaelis-
Menten kinetics.
v Rate of drug metabolism
V
K C
max
m
= = +
[ ] C
[ ]
In most clinical situations, the concentration of the drug, [C], is
much less than the Michaelis constant, Km, and the Michaelis-
Menten equation reduces to
v Rate of drug metabolism
V C
K
max
m
= = [ ]
That is, the rate of drug metabolism and elimination is directly pro-
portional to the concentration of free drug, and first-order kinetics
is observed (Figure 1.15). This means that a constant fraction of
drug is metabolized per unit of time (that is, with each half-life,
the concentration decreases by 50%). First-order kinetics is also
referred to as linear kinetics.
2. Zero-order kinetics: With a few drugs, such as aspirin, ethanol,
and phenytoin, the doses are very large. Therefore, [C] is much
greater than Km, and the velocity equation becomes
v Rate of drug metabolism
V C
C
V max = = = max
[ ]
[ ]
The enzyme is saturated by a high free drug concentration,
and the rate of metabolism remains constant over time. This is
called zero-order kinetics (also called nonlinear kinetics). A con-
stant amount of drug is metabolized per unit of time. The rate
of elimination is constant and does not depend on the drug
concentration.

Question 26

Reaction of drug metabolism

Answer 26

Reactions of drug metabolism
The kidney cannot efficiently eliminate lipophilic drugs that readily
cross cell membranes and are reabsorbed in the distal convoluted
tubules. Therefore, lipid-soluble agents are first metabolized into more polar (hydrophilic) substances in the liver via two general sets of reac-
tions, called phase I and phase II (Figure 1.16).
1. Phase I: Phase I reactions convert lipophilic drugs into more polar
molecules by introducing or unmasking a polar functional group,
such as –OH or –NH2
. Phase I reactions usually involve reduc-
tion, oxidation, or hydrolysis. Phase I metabolism may increase,
decrease, or have no effect on pharmacologic activity.
a. Phase I reactions utilizing the P450 system: The phase I
reactions most frequently involved in drug metabolism are cata-
lyzed by the cytochrome P450 system (also called microsomal
mixed-function oxidases). The P450 system is important for the
metabolism of many endogenous compounds (such as ste-
roids, lipids) and for the biotransformation of exogenous sub-
stances (xenobiotics). Cytochrome P450, designated as CYP,
is a superfamily of heme-containing isozymes that are located
in most cells, but primarily in the liver and GI tract.
[1] Nomenclature: The family name is indicated by the Arabic
number that follows CYP, and the capital letter designates
the subfamily, for example, CYP3A (Figure 1.17). A second
number indicates the specific isozyme, as in CYP3A4.
[2] Specificity: Because there are many different genes that
encode multiple enzymes, there are many different P450
isoforms. These enzymes have the capacity to modify a
large number of structurally diverse substrates. In addi-
tion, an individual drug may be a substrate for more than
one isozyme. Four isozymes are responsible for the vast
majority of P450-catalyzed reactions. They are CYP3A4/5,
CYP2D6, CYP2C8/9, and CYP1A2 (Figure 1.17).
Considerable amounts of CYP3A4 are found in intestinal
mucosa, accounting for first-pass metabolism of drugs such
as chlorpromazine and clonazepam.
[3] Genetic variability: P450 enzymes exhibit considerable
genetic variability among individuals and racial groups.
Variations in P450 activity may alter drug efficacy and the
risk of adverse events. CYP2D6, in particular, has been
shown to exhibit genetic polymorphism. CYP2D6 mutations
result in very low capacities to metabolize substrates. Some
individuals, for example, obtain no benefit from the opioid analgesic codeine, because they lack the CYP2D6 enzyme
that activates the drug. Similar polymorphisms have been
characterized for the CYP2C subfamily of isozymes. For
instance, clopidogrel carries a warning that patients who
are poor CYP2C19 metabolizers have a higher incidence
of cardiovascular events (for example, stroke or myocar-
dial infarction) when taking this drug. Clopidogrel is a pro-
drug, and CYP2C19 activity is required to convert it to the
active metabolite. Although CYP3A4 exhibits a greater than
10-fold variability between individuals, no polymorphisms
have been identified so far for this P450 isozyme.
[4] Inducers: The CYP450-dependent enzymes are an
important target for pharmacokinetic drug interactions. One
such interaction is the induction of selected CYP isozymes.
Xenobiotics (chemicals not normally produced or expected
to be present in the body, for example, drugs or environ-
mental pollutants) may induce the activity of these enzymes.
Certain drugs (for example, phenobarbital, rifampin, and
carbamazepine) are capable of increasing the synthesis
of one or more CYP isozymes. This results in increased
biotransformation of drugs and can lead to significant
decreases in plasma concentrations of drugs metabolized
by these CYP isozymes, with concurrent loss of pharma-
cologic effect. For example, rifampin, an antituberculosis
drug (see Chapter 41), significantly decreases the plasma
concentrations of human immunodeficiency virus (HIV) pro-
tease inhibitors, thereby diminishing their ability to suppress
HIV replication. St. John’s wort is a widely used herbal prod-
uct and is a potent CYP3A4 inducer. Many drug interactions
have been reported with concomitant use of St. John’s wort.
Figure 1.18 lists some of the more important inducers for
representative CYP isozymes. Consequences of increased
drug metabolism include 1) decreased plasma drug con-
centrations, 2) decreased drug activity if the metabolite is
inactive, 3) increased drug activity if the metabolite is active,
and 4) decreased therapeutic drug effect.
[5] Inhibitors: Inhibition of CYP isozyme activity is an impor-
tant source of drug interactions that lead to serious adverse
events. The most common form of inhibition is through com-
petition for the same isozyme. Some drugs, however, are
capable of inhibiting reactions for which they are not sub-
strates (for example, ketoconazole), leading to drug inter-
actions. Numerous drugs have been shown to inhibit one
or more of the CYP-dependent biotransformation pathways
of warfarin. For example, omeprazole is a potent inhibi-
tor of three of the CYP isozymes responsible for warfarin
metabolism. If the two drugs are taken together, plasma
concentrations of warfarin increase, which leads to greater
anticoagulant effect and increased risk of bleeding.
[Note: The more important CYP inhibitors are erythromycin,
ketoconazole, and ritonavir, because they each inhibit several
CYP isozymes.] Natural substances may also inhibit drug
metabolism. For instance, grapefruit juice inhibits CYP3A4 and leads to higher levels and/or greater potential for toxic
effects with drugs, such as nifedipine, clarithromycin, and
simvastatin, that are metabolized by this system.
b. Phase I reactions not involving the P450 system: These
include amine oxidation (for example, oxidation of catechol-
amines or histamine), alcohol dehydrogenation (for example,
ethanol oxidation), esterases (for example, metabolism of
aspirin in the liver), and hydrolysis (for example, of procaine).
2. Phase II: This phase consists of conjugation reactions. If the
metabolite from phase I metabolism is sufficiently polar, it can be
excreted by the kidneys. However, many phase I metabolites are
still too lipophilic to be excreted. A subsequent conjugation reac-
tion with an endogenous substrate, such as glucuronic acid, sulfu-
ric acid, acetic acid, or an amino acid, results in polar, usually more
water-soluble compounds that are often therapeutically inactive. A
notable exception is morphine-6-glucuronide, which is more potent
than morphine. Glucuronidation is the most common and the most
important conjugation reaction. [Note: Drugs already possessing
an –OH, –NH2
, or –COOH group may enter phase II directly and
become conjugated without prior phase I metabolism.] The highly
polar drug conjugates are then excreted by the kidney or in bile.b. Phase I reactions not involving the P450 system: These
include amine oxidation (for example, oxidation of catechol-
amines or histamine), alcohol dehydrogenation (for example,
ethanol oxidation), esterases (for example, metabolism of
aspirin in the liver), and hydrolysis (for example, of procaine).
2. Phase II: This phase consists of conjugation reactions. If the
metabolite from phase I metabolism is sufficiently polar, it can be
excreted by the kidneys. However, many phase I metabolites are
still too lipophilic to be excreted. A subsequent conjugation reac-
tion with an endogenous substrate, such as glucuronic acid, sulfu-
ric acid, acetic acid, or an amino acid, results in polar, usually more
water-soluble compounds that are often therapeutically inactive. A
notable exception is morphine-6-glucuronide, which is more potent
than morphine. Glucuronidation is the most common and the most
important conjugation reaction. [Note: Drugs already possessing
an –OH, –NH2
, or –COOH group may enter phase II directly and
become conjugated without prior phase I metabolism.] The highly
polar drug conjugates are then excreted by the kidney or in bile.

Question 27

DRUG CLEARANCE BY THE KIDNEY

Glomerular filtration

Answer 27

A. Renal elimination of a drug
Elimination of drugs via the kidneys into urine involves the processes
of glomerular filtration, active tubular secretion, and passive tubular
reabsorption.
1. Glomerular filtration: Drugs enter the kidney through renal arter-
ies, which divide to form a glomerular capillary plexus. Free drug
(not bound to albumin) flows through the capillary slits into the
Bowman space as part of the glomerular filtrate (Figure 1.19). The
glomerular filtration rate (GFR) is normally about 125 mL/min but
may diminish significantly in renal disease. Lipid solubility and pH
do not influence the passage of drugs into the glomerular filtrate.
However, variations in GFR and protein binding of drugs do affect
this process.

Question 28

Proximal tubular secretion

Answer 28

Proximal tubular secretion: Drugs that were not transferred into
the glomerular filtrate leave the glomeruli through efferent arterioles,
which divide to form a capillary plexus surrounding the nephric lumen
in the proximal tubule. Secretion primarily occurs in the proximal
tubules by two energy-requiring active transport systems: one for
anions (for example, deprotonated forms of weak acids) and one for
cations (for example, protonated forms of weak bases). Each of these
transport systems shows low specificity and can transport many
compounds. Thus, competition between drugs for these carriers can
occur within each transport system. [Note: Premature infants and
neonates have an incompletely developed tubular secretory mecha-
nism and, thus, may retain certain drugs in the glomerular filtrate.]

Question 29

Distal tubular reabsorption

Answer 29

As a drug moves toward the dis-
tal convoluted tubule, its concentration increases and exceeds
that of the perivascular space. The drug, if uncharged, may dif-
fuse out of the nephric lumen, back into the systemic circulation.
Manipulating the urine pH to increase the fraction of ionized drug
in the lumen may be done to minimize the amount of back diffusion
and increase the clearance of an undesirable drug. As a general
rule, weak acids can be eliminated by alkalinization of the urine,
whereas elimination of weak bases may be increased by acidifica-
tion of the urine. This process is called “ion trapping.” For example,
a patient presenting with phenobarbital (weak acid) overdose can
be given bicarbonate, which alkalinizes the urine and keeps the
drug ionized, thereby decreasing its reabsorption.

Question 30

Role of drug metabolism

Answer 30

Role of drug metabolism: Most drugs are lipid soluble and, without
chemical modification, would diffuse out of the tubular lumen when
the drug concentration in the filtrate becomes greater than that in the
perivascular space. To minimize this reabsorption, drugs are modi-
fied primarily in the liver into more polar substances via phase I and
phase II reactions (described above). The polar or ionized conjugates
are unable to back diffuse out of the kidney lumen (Figure 1.20).

Question 31

CLEARANCE BY OTHER ROUTES

Answer 31

Drug clearance may also occur via the intestines, bile, lungs, and breast
milk, among others. Drugs that are not absorbed after oral administration
or drugs that are secreted directly into the intestines or into bile are elimi-
nated in the feces. The lungs are primarily involved in the elimination of
anesthetic gases (for example, isoflurane). Elimination of drugs in breast
milk may expose the breast-feeding infant to medications and/or metabo-
lites being taken by the mother and is a potential source of undesirable
side effects to the infant. Excretion of most drugs into sweat, saliva, tears,
hair, and skin occurs only to a small extent. Total body clearance and
drug half-life are important measures of drug clearance that are used to
optimize drug therapy and minimize toxicity.

Question 32

Total body clearance

Answer 32

Total body clearance
The total body (systemic) clearance, CLtotal, is the sum of all clear-
ances from the drug-metabolizing and drug-eliminating organs. The
kidney is often the major organ of elimination. The liver also contrib-
utes to drug clearance through metabolism and/or excretion into the
bile. Total clearance is calculated using the following equation:
CLtotal = + CLhepatic CLrenal + + CLpulmonary o CL ther
where CLhepatic + CLrenal are typically the most important.

Question 33

Clinical situations resulting in changes in drug half-life

Answer 33

When a patient has an abnormality that alters the half-life of a drug,
adjustment in dosage is required. Patients who may have an increase
in drug half-life include those with 1) diminished renal or hepatic blood
flow, for example, in cardiogenic shock, heart failure, or hemorrhage;
2) decreased ability to extract drug from plasma, for example, in renal
disease; and 3) decreased metabolism, for example, when a con-
comitant drug inhibits metabolism or in hepatic insufficiency, as with
cirrhosis. These patients may require a decrease in dosage or less
frequent dosing intervals. In contrast, the half-life of a drug may be
decreased by increased hepatic blood flow, decreased protein bind-
ing, or increased metabolism. This may necessitate higher doses or
more frequent dosing intervals.

Question 34

DESIGN AND OPTIMIZATION
OF DOSAGE REGIMEN

Answer 34

To initiate drug therapy, the clinician must select the appropriate route
of administration, dosage, and dosing interval. Selection of a regimen
depends on various patient and drug factors, including how rapidly thera-
peutic levels of a drug must be achieved. The regimen is then further
refined, or optimized, to maximize benefit and minimize adverse effects.

Question 35

Continuous infusion regimens

Answer 35

Therapy may consist of a single dose of a drug, for example, a sleep-
inducing agent, such as zolpidem. More commonly, drugs are con-
tinually administered, either as an IV infusion or in oral fixed-dose/
fixed-time interval regimens (for example, “one tablet every 4 hours”).
Continuous or repeated administration results in accumulation of the
drug until a steady state occurs. Steady-state concentration is reached
when the rate of drug elimination is equal to the rate of drug administra-
tion, such that the plasma and tissue levels remain relatively constant.

Question 36

Plasma concentration of a drug following IV infusion:

Answer 36

Plasma concentration of a drug following IV infusion: With
continuous IV infusion, the rate of drug entry into the body is con-
stant. Most drugs exhibit first-order elimination, that is, a constant
fraction of the drug is cleared per unit of time. Therefore, the rate of
drug elimination increases proportionately as the plasma concen-
tration increases. Following initiation of a continuous IV infusion,
the plasma concentration of a drug rises until a steady state (rate of
drug elimination equals rate of drug administration) is reached, at
which point the plasma concentration of the drug remains constant.
a. Influence of the rate of infusion on steady-state concen-
tration: The steady-state plasma concentration (Css) is directly
proportional to the infusion rate. For example, if the infusion
rate is doubled, the Css is doubled (Figure 1.21). Furthermore,
the Css is inversely proportional to the clearance of the drug.
Thus, any factor that decreases clearance, such as liver or kid-
ney disease, increases the Css of an infused drug (assuming
Vd
remains constant). Factors that increase clearance, such as
increased metabolism, decrease the Css.

Question 37

Time required to reach steady state drug concentration

Answer 37

b. Time required to reach the steady-state drug concentra-
tion: The concentration of a drug rises from zero at the start of
the infusion to its ultimate steady-state level, Css (Figure 1.21).
The rate constant for attainment of steady state is the rate con-
stant for total body elimination of the drug. Thus, 50% of Css of a
drug is observed after the time elapsed, since the infusion, t, is
equal to t1/2, where t1/2 (or half-life) is the time required for the drug
concentration to change by 50%. After another half-life, the drug
concentration approaches 75% of Css (Figure 1.22). The drug con-
centration is 87.5% of Css at 3 half-lives and 90% at 3.3 half-lives.
Thus, a drug reaches steady state in about four to five half-lives.
The sole determinant of the rate that a drug achieves steady
state is the half-life (t1/2) of the drug, and this rate is influenced
only by factors that affect the half-life. The rate of approach to
steady state is not affected by the rate of drug infusion. When the
infusion is stopped, the plasma concentration of a drug declines
(washes out) to zero with the same time course observed in
approaching the steady state (Figure 1.22).

Question 38

Fixed-dose/fixed-time regimens

Answer 38

Administration of a drug by fixed doses rather than by continuous
infusion is often more convenient. However, fixed doses of IV or oral
medications given at fixed intervals result in time-dependent fluctua-
tions in the circulating level of drug, which contrasts with the smooth
ascent of drug concentration observed with continuous infusion.

Question 39

Multiple IV injections

Answer 39

When a drug is given repeatedly at regular
intervals, the plasma concentration increases until a steady state
is reached (Figure 1.23). Because most drugs are given at intervals shorter than five half-lives and are eliminated exponentially with
time, some drug from the first dose remains in the body when the
second dose is administered, some from the second dose remains
when the third dose is given, and so forth. Therefore, the drug accu-
mulates until, within the dosing interval, the rate of drug elimination
equals the rate of drug administration and a steady state is achieved.

a. Effect of dosing frequency: With repeated administration at
regular intervals, the plasma concentration of a drug oscillates
about a mean. Using smaller doses at shorter intervals reduces
the amplitude of fluctuations in drug concentration. However,
the Css is affected by neither the dosing frequency (assuming
the same total daily dose is administered) nor the rate at which
the steady state is approached.
b. Example of achievement of steady state using different
dosage regimens: Curve B of Figure 1.23 shows the amount
of drug in the body when 1 unit of a drug is administered IV and
repeated at a dosing interval that corresponds to the half-life
of the drug. At the end of the first dosing interval, 0.50 units
of drug remain from the first dose when the second dose is
administered. At the end of the second dosing interval, 0.75
units are present when the third dose is given. The minimal
amount of drug remaining during the dosing interval progres-
sively approaches a value of 1.00 unit, whereas the maximal
value immediately following drug administration progressively
approaches 2.00 units. Therefore, at the steady state, 1.00
unit of drug is lost during the dosing interval, which is exactly
matched by the rate of administration. That is, the “rate in”
equals the “rate out.” As in the case for IV infusion, 90% of the
steady-state value is achieved in 3.3 half-lives.

Question 40

Multiple oral administrations

Answer 40

Most drugs that are administered
on an outpatient basis are oral medications taken at a specific
dose one, two, or three times daily. In contrast to IV injection, orally
administered drugs may be absorbed slowly, and the plasma con-
centration of the drug is influenced by both the rate of absorption
and the rate of elimination (Figure 1.24).

Question 41

Optimisation of dose

Answer 41

The goal of drug therapy is to achieve and maintain concentrations
within a therapeutic response window while minimizing toxicity and/
or side effects. With careful titration, most drugs can achieve this goal.
If the therapeutic window (see Chapter 2) of the drug is small (for
example, digoxin, warfarin, and cyclosporine), extra caution should
be taken in selecting a dosage regimen, and monitoring of drug levels
may help ensure attainment of the therapeutic range. Drug regimens
are administered as a maintenance dose and may require a loading
dose if rapid effects are warranted. For drugs with a defined therapeu-
tic range, drug concentrations are subsequently measured, and the
dosage and frequency are then adjusted to obtain the desired levels.

Question 42

Maintenance dose

Answer 42

Maintenance dose: Drugs are generally administered to main-
tain a Css within the therapeutic window. It takes four to five
half-lives for a drug to achieve Css. To achieve a given concentration, the rate of administration and the rate of elimination of the
drug are important. The dosing rate can be determined by know-
ing the target concentration in plasma (Cp), clearance (CL) of the
drug from the systemic circulation, and the fraction (F) absorbed
(bioavailability):
Dosing rate (Target C CL
F
plasma = )( )

Question 43

Loading dose

Answer 43

Loading dose: Sometimes rapid obtainment of desired plasma
levels is needed (for example, in serious infections or arrhythmias).
Therefore, a “loading dose” of drug is administered to achieve the
desired plasma level rapidly, followed by a maintenance dose to
maintain the steady state (Figure 1.25). In general, the loading
dose can be calculated as
Loading dose=(Vd
)×(desired steady-state plasma concentration)/F
For IV infusion, the bioavailability is 100%, and the equation
becomes
Loading dose = (Vd
) × (desired steady-state plasma concentration)
Loading doses can be given as a single dose or a series of doses.
Disadvantages of loading doses include increased risk of drug tox-
icity and a longer time for the plasma concentration to fall if excess
levels occur. A loading dose is most useful for drugs that have a
relatively long half-life. Without an initial loading dose, these drugs
would take a long time to reach a therapeutic value that corre-
sponds to the steady-state level.