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ONE COMPARTMENT OPEN
MODEL-INTRAVENOUS
BOLUS ADMINISTRATION-6
Muhammad Mohsin – Riphah Institute of Pharmaceutical Sciences
PHARMACOKINETIC
MODELS
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PHARMACOKINETIC MODELS
🞂 A model is a hypothesis using mathematical terms to describe
quantitative relationships concisely.
🞂 The handling of a drug by the body can be very complex, as
several processes (such as absorption, distribution,
metabolism, and elimination) work to alter drug concentrations
in tissues and fluids.
🞂 Simplifications of body processes are necessary to predict a
drug’s behavior in the body.
🞂 One way to make these simplifications is to apply mathematical
principles to the various processes.
🞂 To apply mathematical principles, a model of the body must
be selected.
🞂 Pharmacokinetic models are relatively simple mathematical
schemes that represent
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PHARMACOKINETIC MODELS
🞂 The mathematical models are used to describe the absorption,
distribution and elimination of drugs.
🞂 The key parameters in a process are commonly estimated by
fitting the model to the experimental data, known as variables.
🞂 A pharmacokinetic parameter is a constant for the drug that is
estimated from the experimental data.
🞂 For example, estimated pharmacokinetic parameters such as “K”
depend on the method of tissue sampling, the timing of the sample,
drug analysis, and the predictive model selected.
🞂 A pharmacokinetic function relates an independent variable to a
dependent variable, often through the use of parameters.
🞂 For example, a pharmacokinetic model may predict the drug
concentration in the liver 1 hour after an oral administration of a 20-
mg dose. The independent variable is time and the dependent variable
is the drug concentration in the
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PHARMACOKINETIC MODELS
🞂 Such mathematical models can be devised to simulate the rate
processes of drug absorption, distribution, and elimination to
describe and predict drug concentrations in the body as a
function of time.
🞂 Pharmacokinetic models are used to:
🞂 1. Predict plasma, tissue, and urine drug levels with any
dosage regimen
🞂 2. Calculate the optimum dosage regimen for each patient
individually
🞂 3. Estimate the possible accumulation of drugs and/or
metabolites
🞂 4. Correlate drug concentrations with pharmacologic or
toxicological activity
🞂 5. Evaluate differences in –the
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PHYSIOLOGIC PHARMACOKINETIC MODELS
🞂 These models, also known as blood flow or perfusion
models, are pharmacokinetic models based on known
anatomic and physiologic data.
🞂 The models describe the data kinetically, with the
consideration that blood flow is responsible for
distributing drug to various parts of the body.
🞂 Uptake of drug into organs is determined by the
binding of drug in these tissues.
🞂 In contrast to an estimated tissue volume of
distribution, the actual tissue volume is used.
🞂 Because there are many tissue organs in the body, each
tissue volume must be obtained and its drug
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PHYSIOLOGIC PHARMACOKINETIC MODELS
🞂 PBPK Models divides a body organ into three parts: capillary
vessels, extracellular space, and intracellular space
🞂 Allows extrapolation outside the range of data to deal with altered
physiology (disease states).
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Drug Transport within the
Organ/Tissue
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PHYSIOLOGIC PHARMACOKINETIC MODELS
🞂 In its simplest form, a physiologic pharmacokinetic
model considers the drug to be blood flow limited.
🞂 Drugs are carried to organs by arterial blood and leave
organs by venous blood.
🞂 Differential mass balance equations are written for each
compartment to describe the inflow, outflow, accumulation,
and disappearance of drug, and are solved simultaneously
with the aid of a computer.
🞂 Uptake of drug into the tissues is rapid, and a constant
ratio of drug concentrations between the organ and the
venous blood is quickly established
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PHYSIOLOGIC PHARMACOKINETIC MODELS
Cart,Qt Tissue C ven
- Compartment
Blood
Non eliminating tissue
• This ratio is the organ
tissue/blood partition coefficient :
Ptissue= Ctissue / Cblood
• where Ctissue ( Ct ) is the concentration of drug in the tissue and
Cblood in the blood. P is the partition coefficient.
🞂 The magnitude of the partition coefficient can vary depending on the
drug and on the type of tissue. • for example: Adipose tissue has a
high partition for lipophilic drugs.
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PHYSIOLOGIC PHARMACOKINETIC MODELS
Cart,Qt Tissue Compartment C ven
Blood
Drug Eliminated
A typical eliminating tissue organ
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PHYSIOLOGIC PHARMACOKINETIC MODELS
Blood flow to organ in physiologic pharmacokinetic model
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PHYSIOLOGIC PHARMACOKINETIC MODELS
An abbreviated PBPK model
•The tissues of the model are linked by the systemic
circulation.
•Arterial blood delivers drug to the tissues and the
venous blood leaving the tissue is then returned to
the systemic circulation.
•The concentration in arterial blood is Ca and that in
the venous blood leaving a tissue Cvt.
•Drug elimination may occur as the blood flows
through the kidney (shown) and liver.
•The physiological parameters used in the model are
tissue blood flow (Qt) and tissue volume (Vt).
•This model shows only the lungs, heart, and the
kidney. A typical model may consist of around 7–15
tissues.
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PHYSIOLOGIC PHARMACOKINETIC MODELS
A full PBPK model
This model consists of 11 specific tissues
and the remaining tissues grouped as
“Others.”
In this model, elimination is modeled
from the liver with a rate equal to the
product of the unbound drug
concentration and the drug’s intrinsic
metabolic clearance (Clint).
It is assumed that there is no renal
elimination.
Oral absorption is modeled as a first-
order process controlled by
the absorption rate constant (ka),
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PHYSIOLOGIC PHARMACOKINETIC MODELS
(Merits and Demerits)
🞂 The model would potentially predict realistic tissue
drug concentrations, which the two-compartment
model fails to do.
🞂 Unfortunately, much of the information required for
adequately describing a physiologic pharmacokinetic
model are experimentally difficult to obtain.
🞂 In spite of this limitation, the physiologic
pharmacokinetic model does provide much better
insight into how physiologic factors may change drug
distribution from one animal species to another.
🞂 Other major differences are described below
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PHYSIOLOGIC PHARMACOKINETIC MODELS
(Merits and Demerits)
🞂 First, no data fitting is required in the perfusion
model. Drug concentrations in the various
tissues are predicted by organ tissue size, blood
flow, and experimentally determined drug
tissue–blood ratios (ie, partition of drug
between tissue and blood).
🞂 Second, blood flow, tissue size, and the drug
tissue–blood ratios may vary due to certain
pathophysiologic conditions. Thus, the effect of
these variations on drug distribution must be
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PHYSIOLOGIC PHARMACOKINETIC MODELS
(Merits and Demerits)
🞂 Third, and most important of all, physiologically based
pharmacokinetic models can be applied to several
species, and, for some drugs, human data may be
extrapolated. Extrapolation from animal data is not
possible with the compartment models, because the
volume of distribution in such models is a
mathematical concept that does not relate simply to
blood volume and blood flow.
🞂 To date, numerous drugs (including digoxin, lidocaine,
methotrexate, and thiopental) have been described with
perfusion models. Tissue levels of some of these drugs
cannot be predicted
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ONE COMPARTMENT OPEN
MODEL-INTRAVENOUS
BOLUS ADMINISTRATION-7
Muhammad Mohsin – Riphah Institute of Pharmaceutical Sciences
PHARMACOKINETIC
MODELS
COMPARTMENT MODELS
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COMPARTMENT MODELS
🞂 A basic type of model used in pharmacokinetics is the
compartmental model, which is categorized by the number of
compartments needed to describe the drug’s behavior in the
body.
🞂 There are one-compartment, two-compartment, and multi-
compartment models.
🞂 The compartments do not represent a specific tissue or fluid but
may represent a group of similar tissues or fluids. These models
can be used to predict the time course of drug concentrations in
the body.
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COMPARTMENT MODELS
🞂 A compartment is an imaginary unit that is used to represent a group of
tissues with similar rates of drug distribution.
🞂 The specific tissues that make up a compartment are unknown, and the
number of compartments selected for a particular drug is based on the
behavior of the plasma concentrations observed over time.
🞂 A compartment is a homogeneous unit: The drug concentration is uniform throughout
at all times.
🞂 One of the compartments in any model is the central compartment, which always
consists of the plasma and tissues that take up the drug rapidly.
🞂 The concentration of drug in the central compartment is always equal to
concentration routinely measured in vivo, the plasma concentration.
🞂 The organs of drug elimination are well-perfused tissues. Thus, elimination is
usually, although not always, assumed to occur from the central
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COMPARTMENT MODELS
🞂 To construct a compartmental model as a representation of the
body, simplifications of body structures are made.
🞂 Organs and tissues in which drug distribution is similar are
grouped into one compartment.
🞂 For example, distribution into adipose tissue differs from
distribution into renal tissue for most drugs. Therefore, these
tissues may be in different compartments.
🞂 The highly perfused organs (e.g., heart, liver, and kidneys) often
have similar drug distribution patterns, so these areas may be
considered as one compartment.
🞂 The compartment that includes blood (plasma), heart, lungs,
liver, and kidneys is usually referred to as the central compartment or
the highly blood-perfused compartment.
🞂 The other compartment that includes fat tissue, muscle tissue,
and cerebrospinal fluid is the peripheral compartment, which is
less well perfused than the central compartment.
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COMPARTMENT MODELS
🞂 The value of any model is determined by how well it predicts
drug concentrations in fluids and tissues.
🞂 Generally, it is best to use the simplest model that accurately
predicts changes in drug concentrations over time.
🞂 If a one-compartment model is sufficient to predict plasma drug
concentrations (and those concentrations are of most interest to
us), then a more complex (two-compartment or more) model is
not needed.
🞂 However, more complex models are often required to predict
tissue drug concentrations.
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COMPARTMENT MODELS
🞂 Rate constants are used to represent the overall rate
processes of drug entry into and exit from the
compartment.
🞂 The model is an open system because drug can be eliminated
from the system. Compartment models are based on linear
assumptions using linear differential equations.
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COMPARTMENT MODELS
(Mammillary Model)
🞂 It consists of one or more peripheral compartments connected to the
central compartment in a manner similar to connection of satellites to
a planet.
🞂 They are joined parallel to the central compartment.
🞂 The central compartment comprises of plasma and highly perfused
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COMPARTMENT MODELS
(Mammillary Model)
🞂 The peripheral compartments or tissue compartments
are those with low vascularity and poor perfusion.
🞂 Distribution of drugs to those compartments is through
blood.
🞂 Movement of drug can be defined by first-order
kinetics.
🞂 The mammillary model is the most common
compartment model used in pharmacokinetics.
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COMPARTMENT MODELS
(Mammillary Model)
🞂 In a two-compartment model, drug can move between the
central or plasma compartment to and from the tissue
compartment.
🞂 Although the tissue compartment does not represent a specific
tissue, the mass balance accounts for the drug present in all the
tissues. In this model, the total amount of drug in the body is
simply the sum of drug present in the central compartment plus
the drug present in the tissue compartment.
🞂 Knowing the parameters of either the one- or two-compartment
model, one can estimate the amount of drug left in the body and
the amount of drug eliminated from the body at any time.
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models are particularly useful when little
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COMPARTMENT MODELS
(CATENARY MODEL)
🞂 The catenary model consists of compartments joined to one
another like the compartments of a train. In contrast, the
mammillary model consists of one or more compartments
around a central compartment like satellites.
🞂 Because the catenary model does not apply to the way most
functional organs in the body are directly connected to the
plasma, it is not used as often as the mammillary model.
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PURPOSES / FUNCTIONS OF
COMPARTMENT MODELS
🞂 The drawing of models has three functions. The model
1. Enables the pharmacokineticist to write differential
equations to describe drug concentration changes in each
compartment,
2. Gives a visual representation of the rate processes, and
3. Shows how many pharmacokinetic constants are necessary
to describe the process adequately.
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ONE COMPARTMENT OPEN
MODEL
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ONE COMPARTMENT OPEN MODEL
🞂 Other Names for ONE COMPARTMENT OPEN
MODEL:
🞂 Monoexponential Disposition Model
🞂 Instantaneous Distribution Equilibrium Models
🞂 The one-compartment model is the most
frequently used model in clinical practice.
🞂 In structuring the model, a visual
representation is helpful. Pharmacokinetic model for a drug
administered by rapid intravenous
🞂 The compartment is represented by an injection.
DB = drug in body;
enclosed square or rectangle, and rates of
drug transfer are represented by straight VD = apparent volume of distribution;
arrows. k = elimination rate constant.
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compartment; the arrow pointing out of the
ONE COMPARTMENT OPEN MODEL
🞂 This model is the simplest because there is only one compartment.
🞂 All body tissues and fluids are considered a part of this compartment.
🞂 Furthermore, it is assumed that after a dose of drug is administered, it
distributes instantaneously to all body areas.
🞂 A large number of drugs do show almost instantaneous equilibration with the
body tissues and are distributed homogeneously throughout the body.
🞂 Note that the word homogeneous does not mean equal concentration in this
discussion. It simply means that an equilibration is reached between the
plasma and the various tissues and fluids in the body and that any change in
the plasma concentration can be attributed to the elimination of drug from
the body rather than uptake by the tissues.
🞂 Of course, as the drug is removed from the plasma, body tissues de-
equilibrate and achieve a new equilibrium.
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ONE COMPARTMENT OPEN MODEL
🞂 However, an instantaneous distribution is not realistically
possible, since the body is composed of a heterogeneous group
of tissues, each of which has a different affinity for the drug
molecules and a different rate of equilibration.
🞂 Tissues which are highly perfused, such as the liver and
kidneys, equilibrate with the drug quickly, whereas bones, fat,
and cartilage will equilibrate very slowly, depending on either
the drug solubility in these phases or the specific drug-tissue
interactions.
🞂 In theory, therefore, a true pharmacokinetic model should have
a rate constant for each tissue undergoing equilibration-such a
model is therefore impossible.
🞂 Fortunately, an empirical approach
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equilibration properties are grouped
ONE COMPARTMENT OPEN MODEL
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ONE COMPARTMENT OPEN MODEL
Schemes and Equations
INTRAVENOUS BOLUS ADMINISTRATION
Semilog graph of the rate of drug elimination in
a one-compartment model.
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ONE COMPARTMENT OPEN MODEL
Schemes and Equations
ORAL ADMINISTRATION
Amount remaining to
Amount Eliminated
be absorbed
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ONE COMPARTMENT OPEN
MODEL-INTRAVENOUS
BOLUS ADMINISTRATION-8
Muhammad Mohsin – Riphah Institute of Pharmaceutical Sciences
ONE COMPARTMENT OPEN
MODEL
Calculation of “K” from
Urinary Excretion Data
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Calculation of “K” from Urinary Excretion Data
🞂 One advantage in using urinary excretion data to analyze a
pharmacokinetic system is the noninvasive nature of such data.
It is much more convenient to collect a urine sample than to
draw the blood periodically.
🞂 Another advantage in using urinary excretion data is that this
allows direct measurements of bioavailability, both absolute and
relative, without the necessity of fitting the data to a
mathematical model.
🞂 The elimination rate constant k may be calculated from urinary
excretion data. In this calculation the excretion rate of the drug
is assumed to be first order.
🞂 The two methods used for this calculation are:
1. Rate Method Muhammad Mohsin – Riphah Institute of Pharmaceutical
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RATE METHOD
•
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RATE METHOD
•
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RATE METHOD
•
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RATE METHOD
•
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RATE METHOD
🞂 An average urinary excretion rate
is then calculated for that
collection period.
🞂 Therefore, the average rate of
urinary drug excretion, Du/t, is
plotted against the time
corresponding to the midpoint of
the collection interval, t*, for the
collection of the urine sample.
🞂 The average value of dDu/dt is
plotted on a semilogarithmic
scale against the time that
corresponds to the midpoint
(average time) of the collection
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RATE METHOD (Example)
🞂 The following urinary excretion data are obtained following
intravenous administration of a 100 mg dose:
Time Urine Volume Drug Conc.
(hrs.) (mL) (μg/mL)
0‒1 200 1.85
1‒3 150 2.86
3‒5 300 0.7
5‒9 700 0.2
🞂 If the volume of distribution is 100 liters, calculate the
i. half-life,
ii. K;
iii. ke,
iv. renal clearance;
v. the half-life in case of anuria, or
vi. plasma concentration at t = 3; and
vii. percent biotransformation in normal subjects.
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RATE METHOD (Example - Hints)
•Time Urine Volume Drug Conc. Time Interval Excretion Rate Midtime of
(hrs.) (mL) (μg/mL) (Δt) hrs. (Du/Dt) collection period
μg/hr t*
0‒1 200 1.85 1 200 x 1.85/1=370 0.5
1‒3 150 2.86
3‒5 300 0.7
5‒9 700 0.2
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ONE COMPARTMENT OPEN
MODEL-INTRAVENOUS
BOLUS ADMINISTRATION-9
Muhammad Mohsin – Riphah Institute of Pharmaceutical Sciences
ONE COMPARTMENT OPEN
MODEL
Calculation of “K” from
Urinary Excretion Data
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SIGMA-MINUS METHOD
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SIGMA-MINUS METHOD
•
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SIGMA-MINUS METHOD
•
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SIGMA-MINUS METHOD
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Comparison of the Rate and the
Sigma-Minus Methods
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Problems in Obtaining Valid
Urinary Excretion Data
🞂 Certain factors can make it difficult to obtain valid
urinary excretion data. Some of these factors are as
follows:
1. A significant fraction of the unchanged drug must be
excreted in the urine.
2. The assay technique must be specific for the
unchanged drug and must not include interference
due to drug metabolites that have similar chemical
structures.
3. Frequent sampling is necessary for a
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Problems in Obtaining Valid
Urinary Excretion Data
4. Urine samples should be collected periodically
until almost all of the drug is excreted. A graph
of the cumulative drug excreted versus time will
yield a curve that approaches an asymptote at
“infinite” time. In practice, approximately seven
elimination half-lives are needed for 99% of the
5. drug to be eliminated.
Variations in urinary pH and volume may cause significant
variation in urinary excretion rates.
6. Subjects should be carefully instructed as to the necessity of
giving a complete urine specimen (ie, completely emptying
the bladder).
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