Introduction to
Pharmacokinetics
Part 1: Basic Concepts
MICHAEL E. BURTON
ave you wondered what happens to a drug
H within the patient's body after it has been admin­
istered? Have you questioned how the medica­
tion finds its way from the site of administration to pro­
duce an effect? This article will review the science of
pharmacokinetics and answer these questions.
In order to understand the importance of pharmacoki­
netics, the definition of this science is required. In addi­
tion, understanding the application of pharmacokinetics
is essential for better comprehension of drug therapy.
Pharmacokinetics has been described as the study and
characterization of the time course of drug absorption,
distribution, metabolism, and elimination, as well as the
relationship of these processes to the intensity and time
course of therapeutic and adverse effects of drugs.
Application of the science of pharmacokinetics to the
collection of clinical research data has produced a clin­
ical health science, clinical pharmacokinetics. One prac­
tical use of this clinical science is to enhance drug dosing
and thereby therapeutics. Individualization of drug ther­
apy using clinical pharmacokinetic methods has been
proven to decrease toxic and subtherapeutic effects,
2
thereby improving therapeutics. Thus, the purpose of
this article is to discuss the basic concepts of phar­
macokinetics. In addition, concepts of bioavailability
and the use of bioavailability data to select drug
MICHAEL E. BURTON, PharmD, is Clinical Pharmacist, Phar­
macology Section (HE), Veterans Administration Med­
ical Center, Dallas, TX, and Clinical Assistant Professor
of Pharmacy, College of Pharmacy, The University of
Texas, Austin, TX.
journal of Pharmacy Technology
products will be discussed. Pharmacokinetic models,
dosing methods, and factors which m a y necessitate
alteration of drug therapy will be discussed so pharmacy
technicians will understand the rationale of dosage
individualization.
This review is meant to be an overview, not an in
depth discussion of pharmacokinetics. M o r e complex
systems often are used in practice to describe the phar­
macokinetic modeling of drugs than those described in
this article. Because of the depth of the subject, the
readers are referred to the references for more detailed
explanation. In addition, a glossary is provided to define
terminology. (All italicized words are included in the
glossary.) Part I of this article will deal with basic con­
1
cepts; part II will address clinical application of phar­
macokinetic methods.
Absorption
Absorption is the process by which a drug enters the
systemic blood circulation; it m a y occur via many
routes of administration. The routes of administration
requiring absorption include oral, intramuscular, sub­
cutaneous, rectal, sublingual, transdermal, and inhala­
tion. The administration of a drug through two other
routes, intravenous and intraarterial (directly into the
systemic blood circulation), does not require absorp­
tion. A drug and the delivery method (e.g., tablet, cap­
sule, injection) must have certain characteristics to
ensure adequate absorption by the desired route of
administration. These characteristics will be discussed
in subsequent paragraphs.
As an example of the effect of the route of adminis­
tration upon absorption, the most c o m m o n route of
Mar/Apr 1986 67
administration, oral, will be discussed. Absorption via
the oral route m a y be influenced b y the characteristics
of the drug, the characteristics of the dosage form, and
gastrointestinal (GI) function. Figure 1 provides a
representation of oral drug absorption and T a b l e 1 out­
3
lines the factors modifying drug a b s o r p t i o n . As seen
in Figure 1, any dosage form must disintegrate into
molecular particles forming a solution before a drug can
cross the lipid membranes (epithelial cell membranes)
of the GI tract. T h e processes of disintegration and dis­
solution depend on the physical properties of both the
drug and the particular type of dosage form. For exam­
ple, disintegration time for tablets depends on tablet
compression and various excipients that facilitate dis­
intestine, the duodenal and jejunal segments are the pre­
dominant absorption sites. S o m e absorption may occur
in the ileal segment. Presentation of a drug to the duode­
num and jejunum is dependent upon the rate of gastric
emptying. Generally, the faster the rate of gastric emp­
tying, the m o r e rapid the rate of absorption. O n c e in
the small intestine, the drug must cross through the lipid
membranes of the epithelial cell to reach the systemic
circulation. Lipid soluble molecules, small hydrophilic
molecules, and ions readily pass through this lipid bar­
rier. S o m e drugs m a y even be metabolized by enzymes
within the epithelial cell before reaching the systemic
circulation. Levodopa is an example of a drug metabo­
lized b y an enzyme present within the epithelial cell. 4

integration. Generally, the rate-limiting step for absorp­

tion is considered to be the dissolution rate. Dissolution
depends upon the salt form of the drug, crystal size, sur­
Absorption takes place through two
face area of the particles, particle size, and manufac­
turing variables. processes, passive diffusion and active
Additional factors m a y limit absorption of the dis­ transport.
solved drug. T h e drug must be stable in stomach acid
and resist enzymatic hydrolysis from pancreatic
enzymes in order to be available for absorption in the Absorption takes place through two processes, pas­
small intestine or stomach. In addition, some drugs may sive diffusion and active transport. Passive diffusion is
complex with gastric content such as food or mucins, a first-order process (absorption is proportional to con-
which reduce the amount of drug available for absorp­
tion. An example of complexation is calcium (a diva­
lent ion and component of milk) forming a complex with
tetracycline, an antibiotic, thus inactivating the tetracy­ Table 1 .
cline and reducing the amount of active drug absorbed. Factors Modifying Drug Absorption
It is the nonionized form of a drug that is absorbed,
Physical properties of the drug
whether in the stomach or the small intestine. Since ioni­ lipid solubility (partition coefficient)
zation is dependent upon pKa (pH at which 5 0 percent pKa (ionization)
solubility
of the drug is ionized), absorption m a y be limited b y
stability (i.e., in gastric fluid, water, air)
this physiochemical property of a drug. For example, molecular weight
acidic drugs m a y be partially absorbed in the stomach Properties of the dosage form
because they are nonionized at gastric pH, even though disintegration time
tablet compression
the stomach is not the primary site for absorption. T h e
excipients added for disintegration
primary site of absorption is the small intestine due to dissolution rate
the large surface area available. Since m a n y drugs are particle surface area
crystal size
either weak acids or bases and not ionized at a pH near
salt form
neutral (pH 7 . 0 ) , the neutral pH of the small intestine manufacturing variables
can facilitate absorption of some drugs. Within the small Properties of lumen fluid
pH
enzymes
complexing or solubilizing agents
viscosity
effects of other drugs
absorbants (activated charcoal)
antacids
complexing agents
Factors affecting gastric transit
motility
gastric emptying
drugs altering peristalsis
Factors at absorption site
surface drug
blood flow membrane permeability (lipid solubility)
Figure 1 . A representation of oral absorption with some of the various factors that carrier-mediated transport (glucose)
may affect drug absorption. For further explanations of factors influencing drug local blood flow
absorption, refer to text. Reproduced with permission from Barr WH. Principles epithelial cell metabolism (levo-dopa)
of biopharmaceutics. Am J Pharmaceut Ed 1968;52:958-81.

68 journal of Pharmacy Technology Mar/Apr 1986

 5
centration; Figure 2 ) . The force that drives drugs Table 2. Disease-Induced Alteration
through the epithelial cell is the concentration difference of Drug Absorption
on either side of the cell membrane. T h e rate of drug
penetration depends on lipid solubility, surface area of Delayed stomach emptying (decreased rate of absorption)
the small intestines, and concentration difference. Active atrophic gastritis
gastric carcinoma
transport or facilitated diffusion, being carrier-dependent pyloric stenosis
processes, have a capacity-limited mechanism for trans­ migraine
gastric ulcer
port of drugs across membranes. A s seen in Figure 2,
pancreatitis
the greater the concentration, the more limited the surgical procedures
absorption of a drug becomes until finally a maximal Enhanced stomach emptying (increased rate of absorption)
rate is reached (i.e., all carriers are employed). celiac disease
calculer cholecystitis
Changes in GI motility m a y alter absorption. Slow­ duodenal ulcer
ing tends to increase absorption, while increasing motil­ stress
ity may decrease absorption. Table 2 outlines disease gastroenterostomy

states that may change GI motility and thus drug Alterations in absorption
6
diarrhea—decreased
absorption. In addition, various drugs can alter GI celiac disease—variable
motility and therefore drug absorption. Some classic Crohn's disease—variable
examples include metoclopramide, which increases GI food—variable
fluid intake (increased volume increase rate and extent
motility, and propantheline or opiate analgesics which of absorption)
slow gastrointestinal motility.

Using research generated by

bioavailability studies, we can
evaluate product absorption or at
least be aware of potential problems
with drug absorption.
With the many factors that may influence absorption,
how are we assured of complete or at least adequate
and consistent drug absorption? Using research gener­
ated by bioavailability studies, we can evaluate prod­
uct absorption or at least be aware of potential problems
with drug absorption.
Bioavailability
The term bioavailability is used to describe the rate
7 9
and extent of absorption. " By comparing a drug prod­
uct to a reference standard, bioavailability can be
directly measured. If the reference standard is com­
pletely absorbed (i.e., intravenous dose), then the evalu­
ation is an absolute bioavailability study. Comparison
of a drug dosage form to another dosage form with the
same chemical composition is called a comparative
bioavailability study. Usually, bioavailability studies
involve giving human subjects a dose of a drug, then
measuring serum concentrations generated from that
dose over a specific time period. The bioavailability of
a product is found by comparing the area under the
serum concentration-time curve ( A U C ) of one formu­
lation with that of the reference product or standard
(Equation 1 ) . The ratio (F, or fraction absorbed) which
results is a decimal and c a n be converted to a percent­
age by multiplying by 1 0 0 .

Extent of absorption (F) =

area under curve ( A U C ) [product]
area under curve ( A U C ) [standard] (Eq. 1)

Generally, A U C is determined by computer fitting of

Concentration
Figure 2. A plot of concentration vs. initial rate of transport that illustrates the
difference between the linear passive diffusion and non-linear active (carrier medi­
ated) transport. As can be seen, carrier-mediated transport reaches a maximal
rate while, theoretically, passive diffusion does not. Most drugs are absorbed by
passive diffusion; thus, absorption across the Gl wall is limited primarily by phys-
iochemical factors and the concentration gradient across the cell membrane.
Reproduced with permission from Rowland M, Tozer T N . Clinical
pharmacokinetics—concepts and applications. Philadelphia: Lea and Febiger,
1980:19.
7 9
data or simpler mathematical methods. "
Comparison of bioavailability of different formula­
tions of a drug is performed by assessing parameters that
represent the rate and exent of absorption. The param­
eters that represent the rate of absorption of any for­
mulation include the time required to reach maximal
concentration and the maximal serum concentration.
The extent of absorption is represented by the A U C (Fig-

journal of Pharmacy Technology Mar/Apr 1986 69

ure 3 ) . Both the rate and extent of absorption must be
similar for different formulations of the same drug for
those formulations to be bioequivalent. For drugs that
are bioinequivalent, there must be a statistically signifi­
cant difference in the rate and extent of absorption, but,
for different formulations of a drug to have therapeu­
tic equivalence, the drugs must have similar clinical
effectiveness and safety. Thus, in determining bioavail­
ability one must discern the ability of a particular dos­
age form of a drug to be absorbed into the systemic
circulation, then compare its absorption characteristics
to the reference standard using the a b o v e three param­
eters. Generally, important differences in bioavailabil­
ity occur with drugs that have steep dose-response
relationships, a poor or narrow therapeutic index, or
those drugs eliminated by capacity-limited biotransfor­
mation (at least a 2 0 percent difference in bioavailabil­
ity is considered important).
Distribution
O n c e a drug crosses the epithelial cell m e m b r a n e of
the GI tract and enters the splanchnic (GI) blood circu­
lation, the drug is distributed to the remainder of the
circulation. T h e rate-limiting step for distribution to the
body is blood flow. O n c e a drug is distributed through­
out the systemic circulation, it m a y diffuse to the
extracellular fluid which bathes cells, bind to plasma
proteins, or bind to and enter red blood cells. Outside
of the systemic circulation and in the extracellular fluid,
a drug may bind to body tissues, drug receptors, or enter
the cell. This distribution of drug can be quantitated to
provide an estimation of the apparent space in the body
that contains the drug. T h e pharmacokinetic parame­
ter which describes this distribution space is called the
volume of distribution. V o l u m e of distribution can be
imagined as the volume of drug in fluid at a specific con­
centration it takes to fill a bucket. T h e distribution o f
each drug for the human b o d y would be represented
by a different size of bucket. Technically, the volume
of distribution is a proportionality constant relating
plasma concentration to the total amount of drug in the
5
body; it may range from 0.04 L / k g to 2 0 L / k g or m o r e .
Volume of distribution ( V ) = d
total amount of drug in the b o d y (dose)
concentration at time 0 (Eq. 2)
T h e above equation describes the relationship of vol­
ume of distribution and dose to serum concentration.
This particular equation assumes a one-compartment
model with instantaneous input of a dose, e.g., an
intravenous bolus. T h u s , if one were to sample the
blood of a patient immediately following an intravenous
dose, volume of distribution could be determined from
8 can be determined. Time to peak concentration and peak height represent rate
the dose and blood (serum) c o n c e n t r a t i o n .
Distribution is dependent upon factors that include
the pKa of a drug (ionization), the partition coefficient
70 journal of Pharmacy Technology
(lipid solubility), blood flow to organs (organ size), and
10
plasma and protein b i n d i n g . Since ionized drugs do
not cross membranes well, drugs that are ionized at the
pH of the b l o o d will not penetrate through the wall of
these small b l o o d vessels called capillaries, and distri­
bution m a y be reduced. Drugs that are not lipid solu­
ble penetrate cell m e m b r a n e barriers poorly. An
example would be penicillin, which is not lipid soluble
and has p o o r penetration of the non-inflamed brain.
Changes in the lipid membranes due to inflammation
improve penicillin distribution to the brain. Disease
states that can change systemic blood flow, such as
myocardial infarction, produce a change in the volume
of distribution. An example of a drug with distributional
changes due to myocardial infarction is lidocaine." Both
plasma and tissue binding can influence the magnitude
12
of volume of distribution. T h e plasma protein bind­
ing affects the amount of free drug available to disperse
into the tissues; the drug bound to tissue can represent
a large pool of drug with the resultant increase in the
magnitude of distribution. T h e relationship of tissue and
plasma protein binding to volume of distribution can
be understood by the following equation:
V d total = V b t e o d + V t i 5 5 u e fraction unbound (blood)
fraction unbound (tissue)
(Eq. 3)
This equation relates the total distribution volume ( V d
total) to the blood volume ( V ) and volume of other b k ) o d
tissues in the b o d y ( V ) plus the fraction of the
tissue
unbound drug in the blood and the tissue. Thus, changes
in binding to proteins in the b l o o d (plasma) will alter
total volume of distribution. Generally, a decrease in
plasma protein binding without a change in tissue bind­
ing will increase volume of distribution (Table 3). Obvi-
I I I I I I I I 1 I I ι ι I I
0 1 2 3 4 S 6 7 β 9 10 11 12 13 14
Time (hours)
Figure 3. A plasma concentration-time curve representing the oral absorption of
a drug. By the evaluation of data found in this graph, estimates of bioavailability
of absorption. The area under the curve (AUC) from the plasma concentrations
determined at the various times represents the extent of absorption. The rate and
extent of absorption represents bioavailability. Comparative bioavailability can be
determined by comparing the rates and extent of absorption between products.
Mar/Apr 1986
ously, changes in tissue binding m a y alter volume of Table 3. Inverse Relationships between
distribution. For example, the greater the tissue bind­ Volume of Distribution and
ing (smaller the fraction unbound), the larger the vol­ Plasma Protein Binding
ume of distribution. Drugs such as digoxin that are
highly tissue bound have large volumes of distribution PLASMA PROTEIN
VOLUME OF DISTRIBUTION BINDING
(7-10 L / k g ) . T h u s , drug ionization, lipid solubility, DRUG (L/kg) (%)

blood flow, and plasma and tissue binding can influence Amitryptyline* 8.3 96.4
a drug's volume of distribution. Digoxin* 3-10 25
Propranolol* 3.9 93.3
Quinidine* 2.7 71
Cimetidine 2.1 19
Procainamide 1.9 16
When patients take multiple Carbamazepine 1.4 82
medications, one drug may decrease Diazepam 1.1 98.7
Phénobarbital 0.88 51
or enhance the metabolism of another Phenytoin 0.64 89
drug. Digitoxin 0.51 90
Theophylline 0.50 56
Gentamicin 0.25 <10
Tolbutamide 0.15 93
Warfarin 0.11 99
Furosemide 0.11 95.9
Metabolism and Elimination
"Highly tissue bound
As soon as the absorption process begins, elimina­
tion starts. Elimination m a y occur by metabolism, then
lipid-soluble) forms. O n c e in these more soluble forms,
excretion of metabolites in the bile or urine; or elimi­
drug metabolites m a y be excreted into the bile. In the
nation m a y occur b y renal excretion. S o m e drugs m a y
intestine these metabolites m a y be excreted in feces or
be eliminated b y other means, such as volatile sub­
they m a y be altered b y enzymes or bacteria to an active
stances exhaled by the lung and drugs eliminated in per­
form and recirculate throughout the b o d y . In addition,
spiration. T h e c o m b i n a t i o n of metabolism a n d / o r
drug metabolites m a y be excreted and possibly reab­
elimination can be quantitated by measurement of drug
sorbed b y the kidney. T h r e e processes m a y affect renal
clearance. Clearance is the rate of elimination b y all
drug elimination: glomerular filtration, tubular secre­
routes compared to the concentration of a drug in a n y
13
tion, and tubular reabsorption. T h e rate of glomerular
biologic fluid. In addition, clearance is additive in that
filtration depends on the volume of plasma filtered by
systemic clearance m a y be a combination of hepatic,
the glomeruli and the unbound concentraton of drug
renal, or other elimination. This rate of elimination may
in the plasma. T h e balance of tubular secretion and
be quantitated under steady state conditions b y Equa­
reabsorption m a y account for a net renal secretion of
tion 4 .
drugs. T h e mechanism of secretion is an active process
that is saturable, while reabsorption is passive.
Clearance (CI) =
Often the metabolic and elimination processes m a y
dosing rate (must be continuous infusion) be altered b y other factors, including other drugs, dis­
14
C s s (drug concentration at steady state) (Eq. 4) ease processes, diet, genetics, nutrition, e t c . W h e n
patients take multiple medications, one drug m a y
where steady state is the point in time that dosing rate decrease or enhance the metabolism of another drug.
of a drug to the systemic circulation equals the rate of A drug m a y decrease the metabolism of another drug
active drug elimination. Generally, this is considered b y competitive or complete inhibition of a particular
to be essentially complete at five times the biologic half- drug metabolizing enzyme. Alternatively, some drugs
life (tVi). enhance the metabolism of a drug b y inducement of
these same enzyme systems. In addition, by inheritance
Steady state = 5 X tVi (Eq. 5) (genetics), some drugs m a y not be metabolized as
rapidly (for example, acetylation enzymes), Thus, many
The primary sites of elimination are the liver and kid­ complex factors can alter the rate of drug metabolism.
ney. Within the liver, biotransformation or metabolism Measurement of metabolic rate can be performed b y
occurs. Most drugs are metabolized to some degree, examination of a serum concentration-time curve (Fig­
usually to inactive metabolites, and then excreted in the ure 4 ) . Elimination can be seen b y the decline of plasma
bile. T h e basic metabolic pathways include oxidation, concentration over time which is measured b y the slope
reduction, conjugation, or hydrolysis. With some drugs, 10
(elimination rate c o n s t a n t ) . In addition, half-life can
multiple pathways m a y be used. Generally, metabolism be measured b y the time it takes for the serum concen­
leads to conversion of drugs to more water-soluble (less trations to decrease by one-half (Figure 4 ) . B y multiply-

journal of Pharmacy Technology Mar/Apr 1986 71

ing volume of distribution ( V ) by elimination rate d
constant ( K J , clearance can be determined (Equation 6).
Clearance (CI) = V
T w o , and preferably three or four, serum drug concen­
trations are used clinically to estimate these values for
a particular patient. In more formal research studies,
multiple serum drug concentration sampling requiring
1 0 - 2 0 samples at different times is performed.
Pharmacokinetic modeling is a
method of describing the processes of
absorption, distribution, and
elimination within the body.
Figure 4 demonstrates a drug with first-order phar­
macokinetics. In other words, serum concentration is
proportional to dose. M a n y drugs behave according to
first-order pharmacokinetics; however, some drugs such
as phenytoin or ethanol (grain alcohol) best fit a
capacity-limited pharmacokinetic model. With capacity-
limited pharmacokinetics there may be a disproportion­
ate rise in serum concentration in response to a dosage
increase. A s can be seen in Figure 5 , serum concentra­
tions decline in a non-linear manner. Dosing of drugs
with capacity-limited metabolism is difficult because a
small dosing change may produce a disproportionate
rise in serum concentration with resultant toxicity.
Use of information obtained from studies of drug
d · K e (Eq. 6)
clearance, distribution, and half-life are helpful in
prediction of dose and dosage interval to obtain max­
imal therapeutic response. (Use of this pharmacokinetic
information about a drug by using clinical pharmacoki­
netics will be discussed in part II.)
Pharmacokinetic Modeling
Pharmacokinetic modeling is a method of describing
the processes of absorption, distribution, and elimina­
tion within the body. Figures 4, 5, and 6 represent differ­
ent modeling methods. Figure 4 represents a linear,
one-compartment model, which is the simplest mathe­
matically to understand. W i t h a one-compartment
model, the b o d y represents one compartment. A drug
that just distributed to the blood volume would fit this
model. However, most drugs distribute to extracellu­
lar water or b o d y tissue and are better described by a
two-compartment model, as seen in Figure 6. In this
model, the b o d y is represented as two compartments,
a central compartment representing blood volume and
a peripheral compartment representing b o d y tissues or
extracellular fluids. Elimination occurs from the central
compartment (Figure 6 ) . It m a y occur from the
peripheral or both compartments, depending on how
a drug is eliminated.

MICHAELIS-MENTEN KINETICS
10
Slope=

5h When Cp«K ,the m

linear portion of the

Iv Bolus
Semilogarithmic
Input Compartment
plot allows estimation of
V m a x ^ m i therefore, use
k-Elimlnatlon Rate Constant this r e p r e s e n t a t i o n at low

< serum concentrations

1 1 1

2
10
Slope of Line Equals -k ( ο

v Slope = -Vn.

5h When C p » K , m

the linear portion

of the L i n e a r plot
allows estimation of
v
m a s · therefore, use
this r e p r e s e n t a t i o n at
hiah serum concentrations

10 11 12 13 14 15
Iv Dose
I Given Instantly Time (hours)
TIME
Figure 4. A plot of serum concentrations vs. time following an instantaneous Figure 5. The upper figure represents a semilogarithmic (log) plot of serum con­
intravenous dose. The linear decline in serum concentralions indicates that this centration vs. time following a dose of a drug displaying capacity-limited (Michaelis-
drug would fit a one-compartment pharmacokinetic model. This means that the Menten) pharmacokinetics. The linear portion o( the graph (serum concentration
body represents a single compartment to which the drug distributes. The concen­ <5) allows estimation of a slope of the line which equals V ( V in text)/K .m a x m m

tration at time zero (C ) may be determined by dividing the intravenous dose by

ç When plotted in a linear fashion (lower plot) - V can be estimated from the
m a i (

the volume of distribution; or, by rearranging the equation, volume of distribution linear portion of the plot. Thus with an adequate number of serum concentrations
may be determined. The slope of the line represents the elimination rate constant following a dose, the parameters V ( V in text) and K can be determined to
m a x m m

(K ). Half-life (tVj) may be determined directly by dividing 0.693 (Ln 2) by K (tV4

e e use for subsequent dosing. These plots demonstrate the non-linearity of capacity-
= 0.693/K ). The concentration at any time after the dose may be determined
5 limited metabolism. Thus, a small increase in a dose of a drug displaying this type
by multiplying C times the natural log θ raised to the negative exponent of Κ mul­
0 of metabolism will produce a greater than proportional increase in serum concen­
tiplied by the time since C . 0 tration because the metabolic rate may be maximal.

72 journal of Pharmacy Technology Mar/Apr 1986

 Mathematical equations from these methods are used
to predict the concentration of a drug at a particular
time. For drugs where precise dosing is necessary to pro­
duce desired response, the prediction of serum concen­
trations is particularly important for accurate dosing.
Drugs requiring precise dosing have a narrow therapeu­
tic index.
Other models include the Michaelis-Menten or meta­
bolic capacity-limited model (Figure 5 ) . This model
describes the interactions of an enzyme system (which
13
is saturable) upon a substrate. In the body, this m a y
represent hepatic drug metabolizing enzymes and a drug
(substrate). This model describes drugs like aspirin,
phenytoin, and ethanol. This model is described by the
Michaelis-Menten equation:
K m + C
where R = rate of elimination, V
bolic rate, C ss = steady state serum concentration, and
K,,, = the serum concentration at which metabolic rate
is one-half maximal.
By definition, at steady state serum concentrations,
the rate of elimination must equal the rate of adminis­
tration. By use of steady state serum concentrations a
dosing rate may be predicted. (More on dosing estima­
tion will be discussed in part II of this article.)
A flow-type model assumes that a fraction of the drug
in the body will be extracted from the blood on each
pass through the eliminating organ and that blood flow
1 I I 1
I I I I I I I I I I
0 1 2 3 -, 5 6 7 8 9 10 11
Time (hours)
Figure 6. A plot of serum concentrations vs. time following an instantaneous
intravenous dose for a drug that fits a two-compartment model. The compartments
include a central compartment representing the blood volume and a peripheral
compartment representing the tissue. Elimination occurs from the central com­
partment. The effects upon a serum concentration distribution are represented
_ < ,
by the term Α β ' and the effects of elimination on a serum concentration by the
term Be~*. The term a represents a distribution rate constant and β represents
an elimination rate constant. From the equation C, = Ae + Be - , a serum con­
centration can be determined at any time (t). The clinical utility of a two-
compartment model is limited to a computer because of mathematical complexity.
journal of Pharmacy Technology
is a determinate of drug clearance (Equation 8 ) . 1 2
Cl = Q · Ε Eq. 8
where CI — clearance, Q = blood flow, and Ε =
extraction ratio (or fraction).
Extraction ratio is described by the equation:
T~ CI intrinsic
Ε —
c
Eq. 9
n
Q + CI intrinsic
where CI intrinsic reflects the inherent ability of the
organ to remove the drug.
This concept is similar to that of the Michaelis-Menten
model. Often, the intrinsic clearance of a drug may
exceed what would be expected as a result of blood flow.
Propranolol and lidocaine are notable examples, in that
the liver so avidly extracts the drug that clearance
ss (Eq. 7) depends on blood flow. Phenytoin can also be described
with this model, in that the intrinsic clearance is low.
m = maximal meta­
W h e n intrinsic clearance is small, clearance is more
dependent upon the intrinsic ability of the liver to clear
a drug and extraction ratio instead of blood flow.
These modeling systems can provide the basis to pre­
dict dosing based on serum concentration data obtained
from a patient. The use of an individual's serum con­
centration data allows better prediction of dosage by
taking into account m a n y factors that m a y alter drug
2
pharmacokinetics.
References
1. Gibaldi M. Biopharmaceutics and clinical pharmacokinetics.
2nd ed. Philadelphia: Lea and Febiger, 1977: vii.
2. Burton ME, Brater DC, Vasko MR. Comparison of drug dos­
ing methods. Clin Pharmacokinet 1985:10:1-37.
3. Barr WH. Principles of biopharmaceutics. Am ] Pharmaceut
Ed 1968;52:958-81.
^ Peripheral 4. Riegelman S, Rowland M. Effect of route of administration on
Distribution drug disposition. / Pharmacokinet Biopharm 1973;1:419-34.
Compartment
5. Rowland M, Tozer TN. Clinical pharmacokinetics: concepts
and applications. Philadelphia: Lea and Febiger, 1980:16-33, 34-47.
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