MODULE 1.1.

Introduction to Pharmacokinetics & These drug delivery systems that release and deliver
Biopharmaceutics (1/2) drug to the site of action such that they produce the
Let us begin obtaining the initial knowledge on this desired therapeutic effect. In addition, drug products
course by defining the terms or concepts that will be are designed specifically to meet the patient’s needs
used in the various modules. Let us discuss them as including palatability, convenience, and safety.
follows:
They can be solids (tablets, capsules), semisolids
BIOPHARMACEUTICS AND RELATED TERMS (ointments, creams), liquids, suspensions, emulsions,
BIOPHARMACEUTICS etc, intended to deliver the active drug for systemic
or local therapeutic activity.
Biopharmaceutics is an area of study that deals with
the factors influencing the bioavailability of a drug in DRUG PRODUCT PERFORMANCE
humans and animals and the use of this information It is defined as the release of the drug substance
to optimize therapeutic activity of drug products. from the drug product either for local drug action or
for drug absorption into the plasma for systemic
Specifically, it will focus on the interrelationship of therapeutic activity.
the physicochemical properties of the drug, the
dosage form (drug product) in which the drug is II. BIOAVAILABILITY AND RELATED CONCEPTS
given, and the route of administration on the rate Bioavailability refers to the measure of systemic
and extent of systemic drug absorption. Please refer availability of a drug. The term is used to describe
to the figure below (Source: Shargel, L and Yu, A. the relative amount of drug from an administered
Applied Biopharmaceutics and Pharmacokinetics, 7th dosage form which enters the systemic circulation
edition. McGraw Hill Education, 2012. Chapter 1). and the rate at which the drug appears in the blood
stream. In short, the term described the rate and
extent of drug input.

Drug input processes involved the liberation of the

drug from its formulation matrix and absorption of
the drug released from the drug product of dosage
form.
Biopharmaceutics provides the scientific basis for
drug product design and drug product development. Liberation is the release of the drug from it's dosage
The basis for these concerns must be derived from a form
biopharmaceutics studies which are conducted Absorption is the process of uptake of the compound
either in vivo or in vitro methods. from the site of administration into the systemic
circulation
In vitro methods are procedures employing test BIOEQUIVALENCE
apparatus and equipment without involving The term refers to the comparison of bioavailabilities
laboratory animals or humans. of different formulations, drug products, or batches
In vivo methods are more complex studies involving of the same drug product.
human subjects or laboratory animals.
Biopharmaceutics involves factors that influence; III. PHARMACOKINETICS AND RELATED CONCEPTS
PHARMACOKINETICS
(1) the design of the drug product
(2) stability of the drug within the drug product Pharmacokinetics is the int of the kinetics of drug
(3) the manufacture of the drug product, absorption, distribution, and elimination
(4) the release of the drug from the drug product (ie, metabolism and excretion).
(5) the rate of dissolution/release of the drug at the
absorption site, and Drug disposition is the term used to describe drug
(6) delivery of drug to the site of action distribution and elimination (which covers
metabolism and excretion). It refers to the loss of
DRUGS drug from the central compartment due to transfer
These are substances intended for use in the into other compartments and/or elimination and
diagnosis, cure, mitigation, treatment, or prevention metabolism.
of disease.
Drug disposition is also referred to as the drug
DRUG PRODUCTS / DOSAGE FORMS output process.
Drug output processes are; Distribution, Metabolism continue after the drug has been tested in clinical
and Excretion trials.

Disposition an important prerequisite for Clinical toxicology is the study of adverse effects of
determination or modification of dosing regimens drugs and toxic substances (poisons) in the body.
for individuals and groups of patient
HOW DO DRUGS ACT?
Drug input and output processes are shown in the At this point of the lesson, let us show how these
figure below. (Source: Allen, L. and Ansel, H. Ansel's concepts are interrelated. The following figures are
Pharmaceutical Dosage Forms and Drug Delivery provided to better understand the relationship of
Systems, 10th edition. Lippincott Williams & Wilkins, the concepts stated above.
Wolters Kluwer, 2014. Chapter 5)

Let us try to answer the questions in image A using

the diagram in image B.

As shown in image B, drug action is not solely

accounted by pharmacokinetics nor
pharmacodynamic characteristics of the drug. In fact,
the drug itself has a contribution to whatever would
Clinical pharmacokinetics is the application of be its fate in the body.
pharmacokinetic methods to drug therapy in patient
care. It involves multidisciplinary approach to The physicochemical properties of the drug, such as
individually optimized dosing strategies based on the lipophilicity, MW, degree of ionization, etc., predict
patient’s disease state and patient-specific the pharmacokinetic fate of the drug material. Let us
considerations recall the concepts we learn from Physical Pharmacy,
that small, unionized, and lipophilic molecules are
Population pharmacokinetics refers to the study of those that can cross the biologic membranes, thus
pharmacokinetic differences of drugs in various can get into the systemic circulation. These
population groups. characteristics then determine the pharmacokinetic
properties that can be exhibited by the molecule. It
IV. PHARMACODYNAMIC AND RELATED CONCEPTS can be predicted that small unionized, lipophilic
Pharmacodynamics is the study of the biochemical molecules can become bioavailable, thus is capable
and physiological effects of drugs on the body. This of being distributed and produce pharmacological
includes the mechanisms of drug action and the actions (pharmacodynamic property).
relationship between drug concentration and effect.
The quality of effects depends on how far the drug
Pharmacodynamics is how a drug interacts go, and it depends on the distribution of the drug.
quantitatively with a drug receptor to produce a On the other hand, the intensity of effect can be
response (effect). attributed to the ability of the drug to interact with
the receptors. But the clearance of the drug also
Receptors are the molecules that interact with contributes to the degree or intensity of effect.
specific drugs to produce a pharmacological effect in Increase in pharmacological effects (toxicity) arise
the body. when the drug elimination is inhibited, but in the
contrary, there will be a decrease in pharmacological
V. TOXICOKINETICS AND RELATED CONCEPTS effect if drug elimination is stimulated. Let us not
Toxicokinetics refers to the application of forget that these events depend also in the
pharmacokinetic principles to the design, conduct, physicochemical properties of the drug molecule.
and interpretation of drug safety evaluation studies
and in validating dose-related exposure in animals. If the drug becomes ionized by virtue of metabolism,
then it will exit the body and its action is terminated.
Toxicokinetic studies are performed in animals But, if in the urine the drug remains to be unionized,
during preclinical drug development and may it will be reabsorbed back into the circulation and
continue to produce not only the desired but also the liberation is slow, then it goes that the next steps
the undesired effect. would also be slow.

MODULE 1.1. Introduction to Pharmacokinetics & So, let's talk about the liberation process.
Biopharmaceutics (2/2)

THE LADMER SYSTEM

LADME stands for Liberation, Absorption,
Distribution, Metabolism and Excretion. These are
the processes that determine the "R", or the
response (it can be the one desired or undesired).
The "R" in the LADMER system is the outcome of the
what the LADME fate is.

The liberation of drug from solid dosage forms

following oral administration involves two steps,
disintegration and dissolution. Only when the drug
becomes available in solution that it could gain
access into the circulation through the process of
absorption.

Please take note that the response is not always the To release the drug from a tablet or capsule matrix,
one that is expected. It could actually range from no it needs to break into small particles (disintegration)
response at all, which could be attributed to no first. This is why a tablet formulation requires an
absorption, or did not reach the site of action or it excipient called disintegrants (e.g. starch, sodium
could have been eliminated without getting into the alginate, try to recall your dosage form days).
circulation. These are the possible fate of the drug as Between a tablet and a capsule, the capsule
it sojourns in the body. formulation disintegrates faster since the powders
are not compressed with pressure unlike the tablets.
The distribution of the drug into the different body
compartments will determine whether a desired or Drugs in powders and granules either suspended or
undesired response will be exhibited. The ability of not in a liquid do not undergo the initial step (which
the drug to reach the site of action results to its is disintegration) but proceed right away to the
pharmacodynamic properties (e.g., ability to bind dissolution step. For the drugs in tablet, capsule,
with receptors or affect other targets for drug powder and granules suspended or not in a liquid
action) which is the RESPONSE. with low solubility, dissolution is the rate-limiting
step. This means that if the dissolution rate is slow,
It is important to note that toxicities, adverse effects the absorption is also slow.
(e.g., hypersensitivity reactions, idiosyncratic
reactions) that goes along with what is desired are For drugs in solution form (syrup, elixir, tincture,
all considered as responses which could be etc), it bypasses the two steps, so its rate limiting
attributed not to a single process but to the step for the bioavailability is absorption.
interrelationship of the entire system (LADMER).
MODULE 1.2. Mathematical Fundamentals in
Based on the diagram, the initial event is the Pharmacokinetics (1/4)
liberation process. This step is considered as the
rate-limiting step in the system. LOGARITHMS AND EXPONENTS
Logarithms and exponents are important
Rate-limiting step refers to the slowest step and mathematical fundamentals that we need to recall.
determines how fast or slow the next steps in the Drug concentrations are sometimes expressed in
process is. If the active material from the drugs is not exponential form, while logarithms are applied in
release, then the succeeding steps cannot proceed. If many pharmacokinetic equations.
Exponents
Consider the following expression:
N = bx (e.g.,1000 = 103)

x, the exponent
b, the base
N, the number when b is raised to the xth power

Review of Laws Governing Exponents

Conversion: log to ln

When the base 10 logarithm scale is used for

expressions containing e

Done using the factor 2.303

Example:
log10 5 = 0.6989
Common Logarithm
ln 5 = 0.6989 x 2.303 = 1.609
It is the exponent to which the base must be raised
to equal a number
MODULE 1.2. Mathematical Fundamentals in
If: N = bx
Pharmacokinetics (2/4)
Then: logb N = x
DIFFERENTIAL AND INTEGRAL CALCULUS
Example
Calculus is an important mathematical tool for
100 = 102
analyzing drug movement quantitatively. Differential
log10 100 = 2
equations are used to relate the concentrations of
drugs in various body organs over time while integral
Note: The number 100 is the antilogarithm of 2.
equations are used to model the cumulative
therapeutic or toxic responses of drugs in the body.
Natural Logarithm
It uses the base e, whose value is 2.718282.
In this part of the lesson, we are going to apply
Related to common logarithms by the equation:
differential and integral equations in
2.303 log10 N = ln N
pharmacokinetic problems.
Things to Know about Logarithms
Differential Calculus
1. A logarithm does not have units
Branch of calculus that involves finding the rate at
2. Dimensionless and is considered a real
which a variable quantity is changing
number
3. The log of 1 is 0
Example: Dissolution of a specific amount of drug in
4. Logarithm of a number less than 1 is a
water
negative number
 The rate at which the drug dissolves is
5. The log of a number greater than 1 is a
determined by the rate of drug diffusing
positive number
away from the surface of the solid drug
 Expressed by Noyes-Whitney Equation (a
Review of Laws Governing Logarithms
differential equation)
 The most common and clinical useful method in
calculating AUC is the trapezoidal rule. The
trapezoidal rule is a numerical method frequently
used in pharmacokinetics to calculate the area under
the plasma drug concentration versus- time curve,
called the area under the curve (AUC).

Differential Calculus and Pharmacokinetics

 The amount or concentration of drug in the The area between time intervals is the area of a
body is a variable quantity (dependent trapezoid and can be calculated with the following
variable), and time is considered to be an formula:
independent variable.
Integral Calculus
 Integration is the reverse of differentiation.
In differentiation, it is breaking a process
down to look at the instantaneous process, At this point of the lesson, you should be able to
whereas integration sums up the compute the AUC from t1-tx.
information from small time intervals to
give a total result over a larger time period. Let's practice the AUC calculation using the
trapezoidal rule method by utilizing the sample
Let us consider the figure below. problem below:

Page 29, chapter 2, Applied Biopharmaceutics and

Pharmacokinetics, 7thEd., Shargel, L., et.al

AREA UNDER THE CURVE (AUC) The first observation time is 0.5 hour, followed by 1,
Area Under the Plasma Level-Time Curve (AUC)is a 2, 3, 4, and 5 hours (See corresponding Cp on the
measurement of the extent of bioavailability of a right side of the table).
drug. It reflects the total amount of active drug that
reaches the systemic circulation. The units for AUC From this data, we can consider five trapezoids, that
are expressed as concentration/time (e.g. mcg x is from 0.5 hour to 1 hour, followed by 1 to 2 hours,
hr/mL or mcg/mL x hr). 2 to 3 hours, 3 to 4 hours, and 4 to 5 hours. Thus, if
we calculate the AUC of this data, it would be
Different Methods of Calculating Area under the presented as;
Curve
1. Counting Method (AUC)0.5−5h= {[ C1+C2/2(t2−t1)] + [C2+C3/2(t3−t2)]
2. Weighing Method + [C3+C4/2(t4−t3)] + [C4+C5/2(t5−t4)] +
3. Using Blood Level Equations [C5+C6/2(t6−t5)]}
4. Trapezoidal Rule Method
This is now your working equation to compute for
the AUC using the trapezoidal rule method.
 time on the x-axis, to result in a concentration vs
Practice on your own with the following guide: time curve.

1. Label the time from 0.5 hr as t1, until 5 hrs Semilogarithmic graphing paper allows plotting of
as t6. Do the same for Concentration, 38.5 the data at logarithmic intervals so that the numbers
mcg/mL as C1, until 4.10 mcg/mL as C6. need not be converted to their corresponding log
2. Try substituting the formula with the given values prior to plotting on the graph. It can be
values. interpreted as log plasma concentration vs time
3. Always apply the rule in performing curve.
mathematical operations.

MODULE 1.2. Mathematical Fundamentals in Straight Line (in a graph)

Pharmacokinetics (3/4)  An expression of the linear relationship of x
GRAPHS: Curve Fitting and Determination of Slope and y.
 Very useful for accurately predicting values
Graphing for which there are no experimental
The construction of a curve or straight line by observations.
plotting observed or experimental data on a graph.
General equation:
Important method of visualizing relationships y = mx + b
between variables. m = slope (gives some idea of the steepness of the
curve)
The Variables b = y intercept
 Independent variable (x)
Placed on the horizontal line in a plane or on the
abscissa (x axis)
Ex: time

 Dependent variable (y)

Placed on the vertical line in the plane, or on the
ordinate (y axis)
Ex: drug concentration

Types of Graphs
In pharmacokinetics, graphs are used to visualize
important relationships between variables from an Determination of the Slope
experimental data. Two types of graphs or graph Slope is equal to Δy/Δx.
papers are usually used in pharmacokinetics. These
are Cartesian or rectangular coordinate (1) and  As the value of m approaches 0, the line
semilogarithmic graph or graph becomes more horizontal.
paper (2).
 As the value of m becomes larger, the line
slopes farther upward or downward,
depending on whether m is positive or
negative, respectively.

 Slope of a Straight Line on a Rectangular

coordinate graph (Zero-order Kel)

Using pharmacokinetic data, time is the independent

variable and is plotted on the abscissa (x axis), Slope of a Straight Line on a Semilog Graph (First-
whereas drug concentration is the dependent order Kel)
variable and is plotted on the ordinate (y axis). To determine the slope (m) of a straight line on
semilog paper graph, the y values must be
In using the standard rectangular coordinate graph, converted to logarithms
we simply plot the concentration on the y-axis and
 4. Percent may have NO units and is expressed
mathematically as a decimal between 0 and 1 or as
0% or 100%, respectively.

5. Graphs should always have the axes (abscissa and

ordinate) PROPERLY LABELED WITH UNITS.

Graphs and Determination of Order MODULE 1.3. Drug Concentration and Its Significance
The relationship between the x and y data will (1/3)
determine the; MEASUREMENT OF DRUG CONCENTRATIONS
 Order of the process, Drug concentrations are an important element in
 Data quality, determining individual or population
 Basic kinetics, pharmacokinetics. Drug concentrations are
 Number of outliers, and; measured in biologic samples, such as;
 Provide basis for an underlying  milk
pharmacokinetic model  saliva
 plasma, and
MODULE 1.2. Mathematical Fundamentals in  urine
Pharmacokinetics (4/4)
IMPORTANT POINTS TO REMEMBER IN UNITS OF Chromatographic and mass spectrometric methods
MEASURE are most frequently employed for drug
1. For an equation to be valid, the units or concentration measurement.
dimensions must be constant on both sides of the
equation: Sampling of Biologic Specimens
Units for Expressing Blood Concentration
Invasive method
Drug concentrations should be expressed as  sampling blood, spinal fluid, synovial fluid,
mass/volume tissue biopsy, or any biologic material
Examples: requiring parenteral or surgical intervention
mcg/mL in the patient
μg/mL Non-invasive method
mg/L  sampling of urine, saliva, feces, expired air,
mg% or mg/dL or any biologic material obtained without
parenteral or surgical intervention
Common Units Used in Pharmacokinetics
Drug Concentrations in Blood, Plasma, or Serum

Measurement of drug and metabolite

concentrations (levels) in the blood, serum, or
plasma is the most direct approach to assessing the
pharmacokinetics of the drug in the body.

2. In using equations with different units, the units

may be added or subtracted as long as they are alike,
but divided or multiplied if they are different.
The blood components are summarized in the table
3. Logarithms and ratios DO NOT HAVE UNITS. below.
 which may be associated with the disposition
(distribution, metabolism and excretion) of the drug.
The earlier curve reflects the distribution, while the
tail represents elimination of the drug. We are using
this portion of the graph in determining the
elimination rate constant (Kel).
Drugs in the plasma are often bound to plasma
proteins, so plasma proteins are removed first from The peak plasma concentration (Cmax), time of the
the plasma before drug concentrations are peak concentration (Tmax) and the area under the
measured. The concentration obtained represent the blood (or serum or
unbound drug. The total plasma drug concentration plasma) concentration–time curve (AUC) are the
is the one which has been measured from unfiltered parameters for assessment and comparison of
plasma. When interpreting bioavailability of the drug.
plasma concentrations, it is important to understand
what type of plasma concentration the data reflect. Other pharmacokinetic and pharmacodynamic
parameters can also be reflected in the plasma
Plasma Drug Concentration-Time Curve concentration versus time curve. This include;
 Generated by obtaining the drug
concentration in plasma samples taken at Minimum Effective Concentration (MEC). The
various time intervals after a drug product is concentration of the drug in the blood that must be
administered achieved to exhibit an adequate response
 Plasma drug concentration (Cp) is plotted
on rectangular coordinate graph paper (or Minimum Toxic Concentration (MTC). Drug serum
semilog paper) versus the time concentrations above this level would be expected
A sample of a plasma drug concentration versus time to produce dose-related toxic effects.
curve if the drug is administered extravascularly is
shown below. Therapeutic window. The concentration of the drug
should be maintained between the MEC and the
MTC to exhibit an adequate response and yet not to
produce dose-related toxicities.

Onset time. The time of the first observable effect, it

can be viewed from the graph by noted the time
where the plasma drug concentration reaches the
MEC.

Duration of action. This is observed from the onset

time until such time that the plasma drug
concentration is within the MEC line.
The y- axis of this graph presents the concentration
of drug in the blood (or serum or plasma), and the x- AUC. It represents the total amount of drug
axis presents the time the samples were obtained absorbed into the circulation following the
following the administration of the drug. When the administration of a single dose of the drug.
drug is first administered (time zero), the blood
concentration of the drug should also be zero. MODULE 1.3. Drug Concentration and Its Significance
(2/3)
It can be viewed from this graph the increasing RATE CONSTANTS and ORDERS OF REACTIONS
amount of drug available in the plasma through the  The RATE of a chemical reaction is the
ascending curve (positive slope of the curve). This velocity with which it occurs. Usually, only
represents the absorption data of the drug. The Cp the parent (or pharmacologically active)
rises up with respect to time as the analysis is drug is measured experimentally. The rate
continued until such peak plasma concentration of a reaction is determined experimentally
(Cmax) is reached. It is important to note the time by measuring the disappearance of a drug
when the Cp is at the maximum. Such time is at given time intervals.
referred to as the tmax.  The ORDER of a reaction is the way in which
the concentration of a drug or reactant in a
The descending curve (negative slope of the curve) chemical reaction affects the rate. It also
represents the decreasing plasma concentration refers to the way in which the
 concentration of a drug or reactants C0 = is the y intercept = drug concentration, when
influences the rate of a chemical reaction or time (t) equals zero or
process.
In pharmacokinetics, two orders are of
importance, the zero order and the first order.

Zero-order Reaction
The drug concentration changes with respect to time
at a constant rate  A linear process means rate of elimination is
C = -k0t + C0 proportional to the drug concentration.
Where:  The elimination processes are not saturated
C = drug concentration at any time and can adapt to the needs of the body, to
k0 = zero-order rate constant (units of concentration reduce accumulation of the drug
per time)  95% of the drugs in use at therapeutic
= is the slope of the line concentrations are eliminated by first order
C0 = is the y intercept elimination kinetics
= drug concentration, when time (t) equals  Amount of drug eliminated may change
zero with the amount of drug in the body, but
Negative sign (-) = indicates that the slope is the fraction of a drug in the body eliminated
decreasing over a given time remains constant
 Amount of drug eliminated for each time  Fraction or percent of drug being removed
interval is constant, regardless of the is the same with a high or a low drug
amount of drug in the body. concentration
 The amount of drug eliminated does not
change with the amount or concentration of Brief Summary of Order of Reactions
drug in the body, but the fraction removed
varies.
 The Cp vs t profile during the elimination
phase is linear. Example: 1.2 mg are
eliminated every hour, independently of the
drug concentration in the body.
 Zero Order elimination is rare.
 Mostly occurring when the elimination
system is saturated.
 An example is the elimination of Ethanol.

First-order Reaction MODULE 1.3. Drug Concentration and Its Significance

 First order kinetics means that the rate of (3/3)
change of drug concentration by any In the determination of the order of reaction (e.g.,
process is directly proportional to the drug absorption or elimination), there are two methods
concentration remaining to undertake that used:
process. 1. Graphical method (as previously discussed)
 In first-order elimination the amount of  If a straight line results when Cp is plotted
drug eliminated in a set of time is directly against t, the reaction is ZERO ORDER.
proportional to the amount of drug in the  The reaction is FIRST ORDER if log Cp vs t
body. gives a straight line.
 The drug concentration changes with 2. Half-life method
respect to time equal the product of the HALF-LIFE (t½)
rate constant and the concentration of drug  Expresses the period of time required for
remaining. the concentration of a drug to decrease by
Equivalent mathematical expression: one half
C = C0 e-kt  Is the time required to decrease the initial
dose of drug by 50% (one half of original
Where: value)
C = drug concentration at any time  Unit: time
k = first-order rate constant (units of reciprocal time,
or time-1)
-k/2.3 = is the slope of the line
  Computed as:
T1/2=0.5C0/K0

Significance of Half-life
 Determine the dosing interval necessary to
obtain the desired CP of the drug.
 Generally, the dosing interval is the same as
t1/2.
 Predict how long it will take a drug to reach
steady-state levels.
 Predict the accumulation of a drug in the
body for a specific dosing interval.
 During multiple dosing or continuous IV
infusion it takes approximately 4-5 half-lives
to reach steady-state levels.
 Predict how long it will take a drug
MODULE 1.4. Pharmacokinetic Models (1/4)
concentration to decrease to a lower
The complexity of the drug state and its movement
concentration.
within tissues and fluids, binding with plasma or
 All drugs are decreased by 96% after 4 half-
cellular components, or are metabolized would
lives.
require the use of mathematical models. "Models"
estimate drug dosing and predict the time course of
First-order Half-life
drug efficacy for a given dose.
 Is constant for a first-order process
 Is related to the first-order rate constant
What is a MODEL?
 No matter what the initial amount or It is a mathematic description of a biologic system
concentration of the drug is, the time and is used to express quantitative relations
required for the amount to decrease by one concisely.
half is constant
 Computed as: What about a COMPARTMENT?
T1/2=0.693/K
It refers to a group of tissues with similar blood flow
and drug affinity, but is not a real physiologic or
anatomic region.

Significance of Compartment
 Used to describe and interpret a set of data
obtained by experimentation
 Used to characterize with reproducibility
the behavior and the fate of a drug in
biological system when given by a certain
route of administration and in a particular
dosage form
PHARMACOKINETIC MODEL
It is a hypothesis using mathematical terms to
describe quantitative relationships.
Zero-order Half-life
 Is not constant for a zero-order process Pharmacokinetic model uses the observed time
 Is proportional to the initial amount or course for drug concentrations in the body and, from
concentration of the drug and is inversely these data, obtains various pharmacokinetic
proportional to the zero-order rate parameters to
constant, K0 predict drug dosing outcomes, pharmacodynamics,
 Because the t.changes periodically as drug and toxicity.
concentration decline, this has little
practical value
Pharmacokinetic parameter VS Pharmacokinetic  Catenary model - consists of compartments
function joined to one another like the
Pharmacokinetic parameter. It is constant for drug compartments of a train
that is estimated from the experimental data (e.g.,
k).
Pharmacokinetic function. Relates an independent
variable (time) to a dependent variable (drug
concentration), often through the use of parameters.

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 Physiologic Pharmacokinetic Model(Flow Model)
4. Correlate drug concentrations with pharmacologic
or toxicologic activity  also known as blood flow or perfusion
5. Evaluate differences in the rate or extent of models
availability between formulations (bioequivalence)  are pharmacokinetic models based on
6. Describe how changes in physiology or disease known anatomic and physiologic data
affect the absorption, distribution, or elimination of  describes the data kinetically, with the
the drug consideration that blood flow is responsible
7. Explain drug interactions for distributing drug to various parts of the
body
CLASSES OF PHARMACOKINETIC MODEL
I. Empirical models
 Are focused on describing the data with the
specification of very few assumptions about
the data being analyzed
 Are practical but not very useful in
explaining the mechanism of the actual
process by which the drug is absorbed,
distributed, and eliminated in the body
 Example: A model used for allometric
scaling, a type of prediction of PK
parameters across diverse species
II. Mechanistic models
 specify assumptions and attempt to
incorporate known factors about the
 systems surrounding the data into the MODULE 1.4. Pharmacokinetic Models (2/4)
model, while describing the available data OPEN ONE-COMPARTMENT MODEL
a. Physiologically based models This part of the module will introduce the concepts
 there is a necessity to sample tissue and of drug distribution and elimination in the simplest
monitor blood flow to the liver in vivo model, the one-compartment open model.
 also requires understanding of the clinical
implication of liver drug concentration, type The one-compartment open model assumes that the
of cell representing the liver in case of body can be described as a single, uniform
biopsy, spatial location of the liver tissue to compartment (one compartment), and that drugs
hepatic blood vessels, liver blood perfusion, can enter and leave the body (open model).
etc.
b. Compartmentally based models
 Mamillary model - estimate the amount of
drug in any compartment of the system
after drug is introduced into a given The figure above shows the instantaneous
compartment. It consists of one or more distribution of the drug depicting the one-
compartments around a central compartment open model. The input and output
compartment like satellites. processes are also indicated. Based on this diagram,
the pharmacokinetic parameters that can be
predicted are: Clearance
 Elimination rate constant (ke) - for drugs  Is a measure of drug elimination from
given via intravascular route the body which encompasses
 Absorption rate constant (ka) and metabolism (biotransformation) and
elimination rate constant (ke) - for drugs excretion
administered via extravascular route  Drug Clearance
o Drug clearance refers to the
In open one-compartment model, If the drug volume of plasma fluid that is
entering the body (input) distributes (equilibrates) cleared of drug per unit time
instantly between the blood and other body fluids or o Fraction of drug removed per
tissues. Drug is not necessarily confined to the unit time
circulatory system. Drug may occupy the entire  Cl = k x VD
extracellular fluid, soft tissue or the entire body.  Clearance can also be computed by
Distribution occurs instantly and not pooled in a area method: Cl = X0 / AUCintegr
specific area.
MODULE 1.4. Pharmacokinetic Models (3/4)
Characteristics of Open One-Compartment Models One-Compartment Model IV Infusion
by Intravascular Routes As compared to IV bolus injection, IV infusion allows
 No absorption precise control of plasma drug concentrations to fit
 Rapid distribution of drug between the individual needs of the patient.
blood stream and tissue
 Equilibrium is instantly obtained Other attributes of IV infusion
 Fall of drug concentration depends on  Maintains an effective constant plasma
excretion and metabolism concentration of drugs with narrow
therapeutic index by eliminating
fluctuations between the peak and through
 IV infusion of drugs, such as antibiotics, may
be given with IV fluids that include
electrolytes and nutrients
 The duration of drug therapy may be
maintained or terminated as needed
Scheme for One Compartment Intravenous Infusion

Pharmacokinetic Parameters: One-

Compartment Model IV Bolus
Elimination rate constant (k)
 Governs the rate at which the drug
concentration in the body declines over
time
 Rate of elimination is a first-order
process
 k = ke+ km
 Elimination rate constant can be
computed using the formula of slope
In IV infusion, the uphill curve represents the
Volume of Distribution
constant amount of the drugs that enters slowly into
 Represents a volume that must be
the body until such time that a steady state
considered in estimating the amount of
concentration is obtained. The rate of input (amount
the drug in the body from
of drug entering the plasma) is said to follow a zero-
concentration of the drug found in the
order pattern since the drug is delivered constantly
sampling compartment
at a specific time (as determined by the rate of
 Apparent Volume of Distribution (VD)
infusion, there is an amount to be delivered per
VD = X0 / C0
time, usually per minute). While the elimination rate
X0 = Dose given by IV bolus
depends on the concentration of the drug available
C0= Extrapolated drug concentration at zero
in the body, thus is said to be first-order.
time
Open One Compartment IV Infusion

Steady state or Plateau Concentration (Css)

At steady state plasma concentration (Css), the rate
of drug leaving the body is equal to the rate of drug
(infusion rate) entering the body.
 Rate of drug input = Rate of drug output A drug that follows the pharmacokinetics of a two-
 infusion rate = elimination rate compartment model does not equilibrate rapidly
Css can be calculated using the equation; throughout the body but distributes into two
Css=R/{Vd/K} compartments - the central and peripheral
compartments.
Since VdK=Cl, so Css={R}/{Cl}
The drug distributes rapidly and uniformly in the
 The time required to reach the Css is central compartment, while it equilibrates more
dependent on the elimination rate constant slowly in the tissue or peripheral compartment. The
(k) rate of drug transfer between the two
compartments is assumed to first-order processes.

One-Compartment Model IV Infusion and Loading There are several possible two-compartment
Dose models. See figure below (Source: Shargel, L. and Yu,
Loading dose (DL), or initial bolus dose of a drug is A. Applied Biopharmaceutics and Pharmacokinetics,
used to obtain concentrations as rapidly as possible 7th edition, McGraw Hill Education, 2016. Chapter
since the steady state plasma concentration is not 6).
attained in a relatively short period of time.


MODULE 1.4. Pharmacokinetic Models (4/4)

TWO-COMPARTMENT OPEN MODEL (Intravenous
bolus injection)
The plasma level–time curve for a drug that follows a
two-compartment model shows that the plasma
drug concentration declines bi-exponentially as the
sum of two first-order processes—distribution and
elimination.

Model A in the figure above is used most often and

describes the plasma level–time curve observed in
the figure below.
  Equilibrium is obtained some later time
after administration
 Steep fall on first part of blood level curve
is due to distribution
 Decline of second part of blood level curve
depends on back distribution of drug from
tissue to blood, excretion and metabolism

The pharmacokinetic parameters that can be

determined using two-open compartment model
are;
X0 = dose of drug administered  elimination rate constant (ke) or LaTeX:
Xc = amount of drug in central compartment \beta and distribution rate constant ( LaTeX:
Xp = amount of drug in peripheral compartment \alpha) - for drugs administered via
K12 = rate constant for transfer of drug from the intravascular route
central compartment to the peripheral  absorption rate constant (ka), elimination
compartment. (The subscript 12 indicates transfer rate constant (ke) or LaTeX: \beta and
from the first [central] to the second [peripheral] distribution rate constant ( LaTeX: \alpha) -
compartment.) for drugs administered via extravascular
K21 = rate constant for transfer of drug from the route
peripheral compartment to the central
compartment. (The subscript 21 indicates transfer Please note: Calculations of ke and LaTeX: \beta will
from the second [peripheral] to the first [central] be discussed in this module, while calculation of ka
compartment. Note: Both K12 and K21 are called will be discussed under Module 3 Lesson 2:
microconstants.) Pharmacokinetics of oral absorption.
K10 = first-order elimination rate constant (similar to
the K used previously), indicating elimination of drug Open Two-Compartment Model
out of the central compartment into urine, feces,  If the drug entering the body does not
etc. instantly distribute between the blood and
those other body fluids or tissues which it
eventually reaches
 Distribution of the drug in blood and other
soft tissues
 Occurs at different rates
 Eventually steady state will be reached
which terminates the distribution phase

Method of Residuals
 Also known as feathering, peeling, or curve
stripping
 This method allows the separation of the
monoexponential constituents of a
The characteristics of the two-open compartment biexponential plot of plasma concentration
model can be described by the figure above. against time and therefore, it is a useful
 No absorption procedure for fitting a curve to the
 Slow distribution of drug between blood experimental data of a drug when the drug
stream and tissue does not clearly follow a one-compartment
model.
 At the end of the module, you will learn to:
1. Compare biopharmaceutic considerations in
drug, drug formulation and patient
2. Explain manufacturing considerations in
drug product design
3. Assess pharmacodynamic consideration in
drug product design

MODULE 2.1. Biopharmaceutic Factors Affecting

TWO-COMPARTMENT OPEN MODEL: Important Drug Product Design
Pharmacokinetic Parameters SPECIFIC OBJECTIVES
Elimination rate constant (β) At the end of the lesson, the students should be able
 Same as the one-compartment model, K to;
 Can be computed using the formula for  Explain the relationship of biopharmaceutic
slope (β slope) factors to drug performance, in vitro and in
Distribution rate constant (α) vivo
 Can be computed using the formula for  Define “rate-limiting step” and discuss how
slope (α slope) it relates to bioavailability of a drug
B (y-intercept of the elimination phase or β)  Differentiate solubility and dissolution
 The regression line for the terminal  Describe the various in vivo and in vitro
exponential or β phase is extrapolated to tests commonly used to evaluate drug
the y axis; the y intercept is equal to B. products
A (y-intercept of the distribution phase or α) Biopharmaceutic Factors Affecting Drug Product
 The regression line for the terminal Design
exponential or α phase is extrapolated to Factors affecting drug bioavailability may be
the y axis; the y intercept is equal to A. categorized broadly into those related to the
β half-life (β1/2) formulation of the drug product and the biological
constraints of the patient.
 The t1/2 for the elimination phase (beta
half-life) can be derived from the following Drugs in solid dosage form taken via oral route
relationship: T1/2β=0.693/β requires a series of steps before it becomes
bioavailable. These steps may involve not only the
Other rate constants in Two-Compartment Model characteristic of the drug itself but also the
physiologic nature of the biological system.
The rate constants for the transfer of drug between
compartments are referred to as microconstants or
transfer constants. A number of pharmacokinetic
parameters may be derived by proper substitution of
rate constants a and b and y intercepts A and B into
the following equations:

MODULE 2. Introduction and Objectives

Biopharmaceutics is the study of the
physicochemical properties of the drug and the drug
product, in vitro, as it relates to the bioavailability of
the drug, in vivo, and its desired therapeutic effect. The above mentioned events are processes that
Biopharmaceutics thus links the physical and could limit the bioavailability of the drug.
chemical properties of the drug and the drug
product to their clinical performance, in vivo. AIM OF BIOPHARMACEUTICS
Consequently, a primary concern in  To adjust the delivery of drug from the drug
biopharmaceutics is the bioavailability of drugs. product in such a manner as to provide
optimal therapeutic activity and safety for
the patient.
Considerations in the design of a drug product to can be found in the presentation below. Click and
deliver the active drug with the desired download the slides. Open the comment boxes for
bioavailability characteristics and therapeutic further discussion of the text or image.
objectives include;
MODULE 2.3 . Formulation Factors Affecting Drug
(1) the physicochemical properties of the drug Performance
molecule, This lesson focuses on the role of formulation
(2) the finished dosage form (eg, tablet, capsule, excipients in the drug product design and how they
etc), will influence drug performance or bioavailability.
(3) the nature of the excipients in the drug product,
(4) the method of manufacturing, and Role of excipients
(5) the route of drug administration
 To provide certain functional properties to
Biopharmaceutic principles provide the basis for the the drug and dosage forms
rational design of drug products. The drug product  Affect product performance in vivo
design is usually based on; The table below list the common excipients used and
 The physical and chemical properties of the their functions in the drug product or
drug substance dosage form (Source: Shargel, L and Yu, A. Applied
 The route of drug administration, including Biopharmaceutics and Pharmacokinetics, 7th edition.
the anatomic and physiologic nature of the McGraw Hill Education, 2016. Chapter 15).
application site (eg, oral, topical, injectable,
implant, transdermal patch, etc)
 Desired pharmacodynamic effect (eg,
immediate or prolonged activity)
 Toxicologic properties of the drug
 Safety of excipients
 Effect of excipients and dosage form on
drug product performance
 Manufacturing processes

MODULE 2.2. Physicochemical Properties of Drugs

Affecting Drug Product Design and Bioavailability
The physical and chemical properties of the drug
substance and excipients generally affect the
dissolution kinetics of drug products. These drug Some FUNCTIONAL PROPERTIES OF EXCIPIENTS
characteristics are very important considerations in include;
the design of drug products.
 Improve the compressibility of the active
The table below provide a quick view of these drug
properties and their effect on drug bioavailability  Stabilize the drug against degradation
(rationale). (Source: Shargel, L and Yu, A. Applied  Decrease gastric irritation
Biopharmaceutics and Pharmacokinetics, 7th edition.  Control the rate of drug absorption
McGraw Hill Education, 2016. Chapter 15)  Increase drug bioavailability'
 Excipients in the drug product may also
affect the dissolution kinetics of the drug,
either by altering the medium in which the
drug is dissolving or by reacting with the
drug itself. The table below presents the
effect of some excipients in the dissolution
kinetics of drugs.

The detailed discussion of the physicochemical

properties of drugs that affect drug product design
 MODULE 2.4. Considerations in the Design of Drug
Products
I. BIOPHARMACEUTICS CONSIDERATIONS

Biopharmaceutics deals with the manufacturing

factors and physicochemical properties influencing
the rate and extent of drug absorption from the site
of administration of a drug. These information is
used to;

(1) anticipate potential clinical problems arising from

poor absorption of a candidate drug and
(2) optimize bioavailability of newly developed
compounds
Effects of Formulation Ingredients (Excipients) on
Drug Absorption Essential elements of the biopharmaceutical
o Increase solubility and therefore increases rate of considerations in drug product design
absorption
o Increase retention time in GIT and therefore (1) studies done to decide the physicochemical
increases the amount of drug to be absorbed nature of the drug to be used, for example, salt and
o Acts as carriers to increase drug diffusion across particle size;
intestinal wall (2) the timing of these studies in relation to the
o May retard drug dissolution and thus reduce drug preclinical studies with the drug;
absorption (3) the determination of the solubility and
dissolution characteristics;
Excipients, though pharmacologically inert, may (4) the evaluation of drug absorption and
change the functionality (performance) of the drug physiological disposition studies; and
substance and the bioavailability of the drug from (5) the design and evaluation of the final drug
the dosage form. The figure below shows the effect formulation
of lubricants in dissolution and absorption.
It is important to note that the drug product should
effectively deliver the active drug at an appropriate
rate and amount to the target receptor site so that
the intended therapeutic effect is achieved. This can
be achieved when the drug traversed the biological
membrane barriers, distributed to wanted areas and
escaped unwanted areas, endured metabolic attack,
and caused an alteration of cellular function. Most
importantly, the finished drug product should meet
the therapeutic objective by delivering the drug with
maximum bioavailability and minimum adverse
effects.
The table below presents the effect of excipients on
the pharmacokinetic parameters of oral drug II. PHARMACODYNAMIC CONSIDERATIONS
products
In drug product design, desired therapeutic response
and the type and frequency of adverse reactions to
the drug are considered.

(a) Therapeutic objective. It influences the type of

formulation manufactured
 Nitroglycerin SL for treatment of angina
pectoris - the SL form allows quick release
of the drug and shorter route to the site of
action. This is the desired response to
anginal attack.
 Extended or controlled release form for
prophylactic treatment of chronic disease -
 chronic diseases require long term use of
the drug, so once daily dosing is preferred. Drug absorption from the gastrointestinal (GI) tract
This is achieved by extended or controlled or any other extravascular site is dependent on (1)
release forms. the physicochemical properties of the drug and the
(b) Type and frequency of toxic and/or adverse environment in the small intestine, (2) the dosage
reactions of the drug form used, and (3) the anatomy and physiology of
 Inhaled drugs for local action efficiently the absorption site, such as surface area of the GI
delivered the drug into the lungs, reducing tract, stomach-emptying rate, GI mobility, and blood
the amount needed to reach a therapeutic flow to the absorption site. Extravascular drug
effect at the site of action and thereby delivery is further complicated by variables at the
reducing systemic side effects (inhaled absorption site, including possible drug degradation
corticosteroids have lesser systemic toxicity and significant inter- and intrapatient differences in
than the orally taken drug). the rate and extent of absorption. The variability in
drug absorption can be minimized to some extent by
III. PATIENT CONSIDERATIONS proper biopharmaceutical design of the dosage form
to provide predictable and reliable drug therapy.
Patient compliance to the therapeutic regimen is one Although this module will focus primarily on oral
of the important consideration in designing a drug dosing, the concepts discussed here may be easily
product. Poor patient compliance may result from; extrapolated to other extravascular routes.
 poor product attributes, such as difficulty in
swallowing, disagreeable odor, bitter For an orally administered drug, the absorption
medicine taste, or process depends on the drug dissociating from its
 too frequent and/or unusual dosage dosage form, dissolving in body fluids, and then
requirements diffusing across the biologic membrane barriers of
 pharmacodynamic factors, such as side the gut wall into the systemic circulation.
effects of the drug or an allergic reaction

IV. DRUG PRODUCT CONSIDERATIONS

Drug delivery is another important considerations in

achieving a therapeutic outcome. New approaches
are being developed to deliver drugs safely and
improve efficacy and patient compliance. The slide
presentation below presents the biopharmaceutic
characteristics of a variety of dosage forms.

The drug from a drug product is effectively and

efficiently delivered to the desired area or site of MODULE 3. Learning Objectives
action through a particular route. The detailed Module Learning Outcomes and Outline Topics
discussion of the routes of administration in the Lesson 1 – Basic Principles of Drug Absorption
context of biopharmaceutics are discussed in the 1. Review the anatomy and physiology of the
slide presentation. It also includes the GI tract, and other sites of absorption;
Biopharmaceutic considerations of drug products 2. Describe the physicochemical and
given via different route. physiologic factors influencing drug
absorption;
MODULE 3. Module Introduction
ABSORPTION Lesson 2 – Pharmacokinetics of Oral Absorption
The aim of this module is to study the kinetics of 1. Differentiate the types of bioavailability;
absorption. Before delving into the details, it is and
important to clarify the definition of absorption. 2. Compute for relative and absolute
bioavailability, and AUC determination.
Traditionally, absorption occurs when drug reaches
the systemic circulation, or sometimes when it MODULE 3.1. Basic Principles of Drug Absorption
reaches the portal vein blood stream. In recent (1/3)
years, a new definition is presented, in which drug is ROUTE OF DRUG ADMINISTRATION
assumed to be absorbed when it leaves the lumen Drugs may be given by parenteral, enteral,
and crosses the apical membrane of the enterocytes inhalation, intranasal, transdermal (percutaneous),
lining the intestine. or intranasal route for systemic absorption. Each
route of drug administration has certain advantages not be able to traverse the cell membrane but,
and disadvantages. The systemic availability and instead, go through gaps or tight junctions between
onset of drug action are affected by blood flow at cells, a process known as paracellular drug diffusion.
the administration site, the physicochemical
characteristics of the drug and the drug product, and
any pathophysiologic condition at the absorption
site. After a drug is systemically absorbed, drug
distribution and clearance follow normal
physiological conditions of the body.
Functionally, cell membranes are semipermeable
partitions that act as selective barriers to the
passage of molecules. The lipid bilayer or unit
membrane theory considers the plasma membrane
to be composed of two layers of phospholipid
between two surface layers of proteins, with the
hydrophilic “head” groups of the phospholipids
facing the protein layers and the hydrophobic “tail”
groups of the phospholipids aligned in the interior.
The lipid bilayer theory explains the observation that
lipid-soluble drugs tend to penetrate cell membranes
As discussed in the previous modules, intravascular more easily than polar molecules.
routes are those that do not require absorption. So
for the purpose of discussion, the routes of
administration that is of concern in this module are
the EXTRAVASCULAR routes. When a drug is
administered by an extravascular route of
administration (eg, oral, topical, intranasal,
inhalation, rectal), the drug must first be absorbed
into the systemic circulation and then diffuse or be
transported to the site of action before eliciting
biological and therapeutic activity. The general
principles and kinetics of absorption from these
extravascular sites follow the same principles as oral
dosing, although the physiology of the site of
administration differs. PASSAGE OF DRUGS ACROSS CELL MEMBRANES
1. Passive Diffusion
NATURE OF CELL MEMBRANES Passive diffusion is the process by which molecules
Many drugs administered by extravascular routes spontaneously diffuse from a region of higher
are intended for local effect. Other drugs are concentration to a region of lower concentration.
designed to be absorbed from the site of This process is passive because no external energy is
administration into the systemic circulation. For expended. Passive diffusion is the major absorption
systemic drug absorption, the drug may cross cellular process for most drugs. According to Fick’s law of
membranes. After oral administration, drug diffusion, drug molecules diffuse from a region of
molecules must cross the intestinal epithelium by high drug concentration to a region of low drug
going either through or between the epithelial cells concentration:
to reach the systemic circulation. The permeability of
a drug at the absorption site into the systemic
circulation is intimately related to the molecular
structure and properties of the drug and to the
physical and biochemical properties of the cell
membranes. Once in the plasma, the drug may act where,
directly or have to cross biological membranes to dQ/dt = rate of diffusion
reach the site of action. Therefore, biological
membranes potentially pose a significant barrier to D = diffusion co-efficient
drug delivery. A = surface area of membrane
K = lipid– water partition coefficient of drug in the
Transcellular absorption is the process of drug biologic membrane that controls drug permeation
movement across a cell. Some polar molecules may h = membrane thickness, and
CGI − Cp = difference between the concentrations of 5. Ion-Pair Formation
drug in the gastrointestinal tract and in the plasma. When the ionized drug is linked with an oppositely
charged ion, an ion pair is formed in which the
2. Carrier-Mediated Transport overall charge of the pair is neutral. This neutral drug
Active Transport complex diffuses more easily across the membrane.
Active transport is a carrier-mediated
transmembrane process that plays an important role
in the gastrointestinal absorption and in renal and MODULE 3.1. Basic Principles of Drug Absorption
biliary secretion of many drugs and metabolites. (2/3)
Active transport is characterized by the ability to ORAL DRUG ABSORPTION
transport drug against a concentration gradient— The oral route of administration is the most common
that is, from regions of low drug concentrations to and popular route of drug dosing. The oral dosage
regions of high drug concentrations. Therefore, this form must be designed to account for extreme pH
is an energy-consuming system. In addition, active ranges, the presence or absence of food, degradative
transport is a specialized process requiring a carrier. enzymes, varying drug permeability in the different
Facilitated Diffusion regions of the intestine, and motility of the
Facilitated diffusion is also a carrier-mediated gastrointestinal tract.
transport system, differing from active transport in
that the drug moves along a concentration gradient Anatomic and Physiologic Considerations
(ie, moves from a region of high drug concentration The enteral system consists of the alimentary canal
to a region of low drug concentration). Therefore, from the mouth to the anus. The major physiologic
this system does not require energy input. However, processes that occur in the GI system are secretion,
because this system is carrier mediated, it is digestion, and absorption. Drugs administered orally
saturable and structurally selective for the drug. pass through various parts of the enteral canal,
Transporters and Carrier-Mediated Intestinal including the oral cavity, esophagus, and various
Absorption parts of the gastrointestinal tract.
Influx and efflux transporters are present in the
brush border and basolateral membrane that will
increase drug absorption (influx transporter) or
decrease drug absorption (efflux transporter).

3. Vesicular Transport
Vesicular transport is the process of engulfing
particles or dissolved materials by the cell.
Pinocytosis refers to the engulfment of small solutes
or fluid, whereas phagocytosis refers to the
engulfment of larger particles or macromolecules,
generally by macrophages. Endocytosis and
exocytosis are the processes of moving specific
macromolecules into and out of a cell, respectively.

Oral Cavity
The oral cavity can be used for the sublingual and
buccal absorption of lipid-soluble drugs. An
advantage of drugs absorbed in the oral cavity is
they can by-pass first pass effect.
4. Pore (Convective) Transport
Very small molecules (such as urea, water, and Esophagus
sugars) are able to cross cell membranes rapidly, as if Very little drug dissolution occurs in the esophagus.
the membrane contained channels or pores. Most drugs should be taken with a full glass
(approximately 8 fluid oz or 250 mL) of water to
ensure that drugs will wash down the esophagus and portion of the small intestine or duodenum region.
be more available for absorption. Generally, the The unique anatomy of the duodenum provides an
bioavailability of drugs is better in patients in the immense surface area for the drug to diffuse
fasted state and with a large volume of water. The passively. The large surface area of the duodenum is
solubility of many drugs is limited, and sufficient fluid due to the presence of valve-like folds in the mucous
is necessary for dissolution of the drug. membrane on which are small projections known as
villi. These villi contain even smaller projections
Stomach known as microvilli, forming a brush border. In
A few fat-soluble, acid-stable drugs may be absorbed addition, the duodenal region is highly perfused with
from the stomach by passive diffusion. The fasting a network of capillaries, which helps maintain a
pH of the stomach is about 2–6. In the presence of concentration gradient from the intestinal lumen
food, the stomach pH is about 1.5–2, due to and plasma circulation.
hydrochloric acid secreted by parietal cells.

Duodenum
This portion of the small intestine is the major site
for passive drug absorption due to both its anatomy,
which creates a high surface area, and high blood
flow. The duodenum is a site where many ester
prodrugs are hydrolyzed during absorption.

Jejunum
This portion of the small intestine generally has
fewer contractions than the duodenum and is
preferred for
drug absorption studies. Gastrointestinal Motility
GI motility tends to move the drug through the
Ileum alimentary canal, so the drug may not stay at the
The ileum is the terminal part of the small intestine. absorption site. For drugs given orally, an anatomic
This portion is not clinically significant for drug absorption window may exist within the GI tract in
absorption studies. which the drug is efficiently absorbed.
An absorption window refers to the segment of the
Colon gastrointestinal tract from which the drug is well
The colon lacks villi and has limited drug absorption absorbed and beyond which the drug is either poorly
due to lack of large surface area, blood flow, and the absorbed or not absorbed at all. After oral
more viscous and semisolid nature of the lumen administration, most drugs are well absorbed in the
contents. Drugs that are absorbed well in this region duodenum and to a lesser extent in the jejunum. A
are good candidates for an oral sustained-release small amount of drug absorption may occur from the
dosage form. ileum.

Rectum Gastric Emptying Time

Drug absorption after rectal administration may be Anatomically, a swallowed drug rapidly reaches the
variable, depending on the placement of the stomach. Eventually, the stomach empties its
suppository or drug solution within the rectum. A contents into the small intestine about 2-3 hours.
portion of the drug dose may be absorbed via the Because the duodenum has the greatest capacity for
lower hemorrhoidal veins, from which the drug the absorption of drugs from the GI tract, a delay in
feeds directly into the systemic circulation; some the gastric emptying time for the drug to reach the
drugs may be absorbed via the superior duodenum will slow the rate and possibly the extent
hemorrhoidal vein, which feeds into the mesenteric of drug absorption, thereby prolonging the onset
veins to the hepatic portal vein to the liver, and be time for the drug.
metabolized before systemic absorption.

MODULE 3.1. Basic Principles of Drug Absorption

(3/3)
Factors Affecting Drug Absorption in the
Gastrointestinal Tract
For most drugs, the optimum site for drug
absorption after oral administration is the upper
 Effect of Food on Gastrointestinal Drug Absorption
The presence of food in the GI tract can affect the
bioavailability of the drug from an oral drug product.
Some effects of food on the bioavailability of a drug
from a drug product include
- Delay in gastric emptying
- Stimulation of bile flow
- A change in the pH of the GI tract
- An increase in splanchnic blood flow
- A change in luminal metabolism of the drug
substance
- Physical or chemical interaction of the meal
with the drug product or drug substance
Factors Affecting Gastric Emptying Time (GET)
Timing of drug administration in relation to meals is
Prolong GET (Delayed Shorten GET (Rapid
often important. Pharmacists regularly advise
Gastric Emptying) Gastric Emptying)
patients to take a medication either 1 hour before or
2 hours after meals to avoid any delay in drug
High fat or protein diet Cold or hot food
absorption.
Gastric ulcers Gastrectomy
Heavy exercise Mild exercise
Double-Peak Phenomenon
Lying on the left side Lying on the right side
Some drugs, such as ranitidine, cimetidine, and
Drugs that impair GI Drugs that enhance GI
dipyridamole, after oral administration produce a
motility motility
blood concentration curve consisting of two peaks.
- Opioids - Cholinergic
This double-peak phenomenon is generally observed
- Anticholinergics agonisdets
after the administration of a single dose to fasted
- Metoclopramide
patients. The rationale for the double-peak
phenomenon has been attributed to variability in
Intestinal Motility
stomach emptying, variable intestinal motility,
A drug may take about 4–8 hours to pass through
presence of food, enterohepatic recycling, or failure
the stomach and small intestine during the fasting
of a tablet dosage form.
state. During the fed state, small intestine transit
time (SITT) may take 8–12 hours. The drug must
have a sufficient time (residence time) at the
absorption site for optimum absorption. In the case
of high motility in the intestinal tract, as in diarrhea,
the drug has a very brief residence time and less
opportunity for adequate absorption.

Perfusion of the Gastrointestinal Tract

Once the drug is absorbed from the small intestine,
it enters via the mesenteric vessels to the hepatic-
portal vein and goes to the liver prior to reaching the
systemic circulation. Any decrease in mesenteric
blood flow, as in the case of congestive heart failure,
will decrease the rate of drug removal from the
intestinal tract, thereby reducing the rate of drug
bioavailability.

Absorption through the Lymphatic System

Absorption of drugs through the lymphatic system
bypasses the liver and avoids the first-pass effect
due to liver metabolism, because the lymphatic
For a drug with high water solubility, dissolution of
vessels drain into the vena cava rather than the
the drug occurs in the stomach, and partial emptying
hepatic-portal vein. The lymphatics are important in
of the drug into the duodenum will result in the first
the absorption of dietary lipids and may be partially
absorption peak. A delay in stomach emptying
responsible for the absorption of some lipophilic
drugs.
results in a second absorption peak as the remainder absorption improves the model significantly or has
of the dose is emptied into the duodenum. been verified experimentally.

EFFECT OF DISEASE STATES ON DRUG ABSORPTION During the absorption phase of a plasma level–time
Drug absorption may be affected by any disease that curve, the rate of drug absorption is greater than the
causes changes in (1) intestinal blood flow, (2) rate of drug elimination. Note that during the
gastrointestinal motility, (3) changes in stomach absorption phase, elimination occurs whenever drug
emptying time, (4) gastric pH that affects drug is present in the plasma, even though absorption
solubility, (5) intestinal pH that affects the extent of predominates. At the peak drug concentration in the
ionization, (6) the permeability of the gut wall, (7) plasma, the rate of drug absorption just equals the
bile secretion, (8) digestive enzyme secretion, or (9) rate of drug elimination, and there is no net change
alteration of normal GI flora. in the amount of drug in the body.
1. Parkinson’s disease may have difficulty
swallowing and greatly diminished
gastrointestinal motility.
2. Patients on tricyclic antidepressants
(imiprimine, amitriptyline, and
nortriptyline) and antipsychotic drugs
(phenothiazines) with anticholinergic side
effects may have reduced gastrointestinal
motility or even intestinal obstructions.
3. Achlorhydric patients may not have
adequate production of acids in the
stomach; stomach HCl is essential for
solubilizing insoluble free bases.
4. HIV–AIDS patients are prone to a number of
gastrointestinal (GI) disturbances, such as
decreased gastric transit time, diarrhea, and
achlorhydria.
5. Congestive heart failure (CHF) patients with
persistent edema have reduced splanchnic
blood flow and develop edema in the bowel Immediately after the time of peak drug absorption,
wall. some drug may still be at the absorption site (ie, in
6. Crohn’s disease: The effect on drug the GI tract or other site of administration).
absorption is unpredictable, although However, the rate of drug elimination at this time is
impaired absorption may potentially occur faster than the rate of absorption, as represented by
because of reduced surface area and thicker the postabsorption phase. When the drug at the
gut wall for diffusion. absorption site becomes depleted, the rate of drug
7. Patients with celiac disease generally have absorption approaches zero. The plasma level–time
an increased rate of stomach emptying and curve (now the elimination phase) then represents
increased permeability of the small only the elimination of drug from the body, usually a
intestine. first-order process. Therefore, during the elimination
8. Microvilli are important for many aspects of phase the rate of change in the amount of drug in
drug absorption, patients with significant the body is described as a first-order process.
blood loss, hypoxemia, or intestinal
ischemia may be reasonably expected to SIGNIFICANCE OF ABSORPTION RATE CONSTANTS
have altered drug oral absorption. The actual drug absorption process may be zero-
order, first-order, or a combination of rate processes
MODULE 3.2. Pharmacokinetics of Oral Absorption that is not easily quantitated. For many immediate-
(1/5) release dosage forms, the absorption process is first-
PHARMACOKINETICS OF ORAL ABSORPTION order due to the physical nature of drug diffusion.
In pharmacokinetics, the overall rate of drug For certain controlled-release drug products, the
absorption may be described as either a first-order rate of drug absorption may be more appropriately
or a zero-order input process. Similar with the rate of described by a zero-order rate constant.
drug distribution and elimination, most
pharmacokinetic models assume first-order The calculation of ka is useful in designing a multiple-
absorption unless an assumption of zero-order dosage regimen. Knowledge of the ka and k values
allows for the prediction of peak and trough plasma OPEN-ONE COMPARTMENT EXTRAVASCULAR
drug concentrations following multiple dosing. MODEL (ORAL ROUTE):
PHARMACOKINETIC PARAMETERS
MODULE 3.2. Pharmacokinetics of Oral Absorption 1) Elimination Rate Constant (K)
(2/5) The elimination rate constant has been denoted by
ZERO-ORDER ABSORPTION MODEL the symbol K or Kel. K is measured by the slope of
Zero-order drug absorption from the dosing site into the terminal portion of the plasma drug
the plasma usually occurs when either the drug is concentration versus time curve, the time when
absorbed by a saturable process or a zero-order absorption no longer has an appreciable effect .
controlled-release delivery system is used.

In this model, drug in the gastrointestinal tract, DGI,

is absorbed systemically at a constant rate, k0. Drug
is simultaneously and immediately eliminated from
the body by a first-order rate process defined by a
first-order rate constant, k.
2) Absorption Rate Constant (Ka)
The absorption rate constant will be represented by
Ka. This value indicates the fraction of drug present
at the absorption site (usually the GI tract) that is
absorbed per unit of time. The usual measurement
of Ka is the percentage of drug absorbed per unit of
As previously discussed in Module 1.4. time. If Ka is greater than one in a time unit, almost
Pharmacokinetic Model (3/4), this model is all of the drug would be absorbed over that time
analogous to that of the administration of a drug by interval.
intravenous infusion. The drug concentration in the
plasma subsequently declines in accordance with a
first-order elimination rate process.

FIRST-ORDER ABSORPTION MODEL

Although zero-order drug absorption can occur,
systemic drug absorption after oral administration of
a drug product (eg, tablet, capsule) is usually
assumed to be a first-order process. This model
assumes a first-order input across the gut wall and
first-order elimination from the body.
METHOD OF RESIDUALS
One way to calculate Ka is to use the method of
residuals, which estimates the plasma drug
concentration plot if absorption were instantaneous
and then uses the difference between the actual and
estimated concentrations to determine Ka. We first
This model applies mostly to the oral absorption of estimate (by back-extrapolation) the straight-line
drugs in solution or rapidly dissolving dosage portion of the curve In the figure below, the
(immediate release) forms such as tablets, capsules, extrapolated portion represents the effect of
and suppositories. In addition, drugs given by elimination alone—as if absorption had been
intramuscular or subcutaneous aqueous injections instantaneous.
may also be described using a first-order process.

After oral administration of a drug product, the drug

is released from the drug product and dissolves into
the fluids of the GI tract. In the case of an
immediate-release compressed tablet, the tablet
first disintegrates into fine particles from which the
drug then dissolves into the fluids of the GI tract.

MODULE 3.2. Pharmacokinetics of Oral Absorption

(3/5)
In the next figure below, let us suppose that A, B,
and C are actual measured concentrations and that A
′, B ′, and C ′ are extrapolated concentrations for the
same times.

MODULE 3.2. Pharmacokinetics of Oral Absorption

(4/5)
TWO-ONE COMPARTMENT EXTRAVASCULAR MODEL
(ORAL ROUTE): PHARMACOKINETIC PARAMETERS
Subtraction of the actual points on the uphill portion
from the corresponding points on the extrapolated
line (e.g., A′ – A, B ′ – B, and C ′ – C) will yield a new
set of plasma drug concentrations for each time
point. These values can be plotted with the
appropriate times, and a line is then drawn that best
fits the new points. This new line is called the
residual as in the figure below.

The slope of the line for these new points gives an

estimate of the absorption rate. Just as the negative
slope of the terminal portion of the plasma
concentration curve equals K, the negative slope of
the residual line equals Ka.

3) Half-life
T1/2=0.693/K

4) Area under the curve

AUC0−∞ = AUC0−Tlast + AUCTlast−∞

5) Clearance 1) Elimination Rate Constant (K or β)

Cl (areamethod) = Xo/AUC0−∞ Same technique and equation as open one
compartment model, IV and EV (oral).
Cl=Vd × K
2) Absorption Rate Constant (Ka)
6) Volume of distribution Same technique by feathering or method of residuals
Vd = Xo / AUC×K like in open-one compartment model, we use the
data points that is below the beta line.
7) Cmax and Tmax
These parameters are determined by visual 3) Distribution Rate Constant (α)
inspection of the peak plasma concentration (Cmax) To compute the distribution rate constant, here is
and its corresponding time (Tmax) like in the figure the step-by-step procedure:
below:
1. Plot the data on a semilog paper, then back
extrapolate the line beta,β (shown as red line in the
image above). The y-intercept is labeled as B.

2. Determine the data points found above the β line

(shown as vertical lines in the image above, only
those found in the downhill curve).

3. Label the data points in the descending curve as

Cp1, Cp2, Cp3, etc.. (these data points are above the
beta line, from peak downwards)

4. Label the data points in the beta line as Cp1', Cp2',

Cp3' , etc...

5. Make a tabular presentation of the labeled data

points (see sample below).

6. Find the Cp" by subtracting the Cp' from the Cp

reading.

7. Once the Cp" has been identified, plot it in the

same graph, time (x) vs Cdiff (y). This is now the
violet line in the image above, in your graph this is
the alpha line (representing the distribution line.

8. Back extrapolate the alpha line to find the y-

intercept of that line, labeled as A.

9. Compute for the distribution rate constant, LaTeX:

\alpha, using the equation above.

MODULE 3.2. Pharmacokinetics of Oral Absorption

(5/5)
BIOAVAILABILITY
Bioavailability factor (F) is the proportion of a drug
substance available for biologic absorption. If the
drug is administered intravascularly orintravenously,
the F equals 1 since it is directly administered into
the blood. But if the drug is administered
extravascularly, as in peroral route, it is below 1,
since some portion of the drug is lost during the
process of administration.