Ms.
Cherry-Ann Faith Baruis
BIOPHARMACEUTICS
INTRODUCTION TO BIOPHARMACEUTICS
Drugs
- These are substances intended for use in the
diagnosis, cure, mitigation, treatment or prevention of
diseases.
- Drugs are given in a variety of dosage forms or drug
products such as solids (tablets, capsules), semisolid,
liquids, suspensions, emulsion, etc., for systemic or local
activity.
- Drug product can be considered to be drug delivery
systems that release and deliver drug to the site of
action that they produce the desired therapeutic effect
and are also designed specifically to meet the patient’s
needs including palatability, convenience and safety.
Drug Product Performance
- The release of drug substance from the drug product
either for local drug action or for drug absorption into the
plasma for systemic therapeutic activity.
- The release of the drug substance from the drug
product leading to bioavailability of the drug substance
and eventually leading to one or more pharmacologic
effect.
Bioavailability
- It refers to the measurement of the rate and extent of
active drug that reaches the systemic circulation.
- means access to the bloodstream
Biopharmaceutics (Bio – life & Pharmaceutics)
- Study concerned with the formulation, manufacture,
stability and effectiveness of pharmaceutical dosage
forms.
- Examines the interrelationship of the physical/ chemical
properties of the drug, the dosage form (drug product) in
which the drug is given, and the route of administration
on the rate and extent of systemic drug absorption.
Sequence of Events
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GSDMSFI | BS Pharmacy 3
Amil and Cirera
The importance of the drug substance and the drug
formulation of absorption, and in vivo distribution of the
drug to the site of action, are described as a sequence of
events that precede elicitation of a drug’s therapeutic
effect.
Critical Manufacturing Variables
- The most important steps in manufacturing process.
Biopharmaceutical Consideration in Drug Product
Design
Biopharmaceutics Involves Factors That Influence
1) The design of the drug product.
2) Stability of the drug within the drug product.
3) The manufacture of the drug product.
4) The release of the drug from the product.
5) The rate of dissolution/ release of the drug at the
absorption site.
6) Delivery of drug to the site of action which may
involve targeting a localized area for action or
systemic absorption of drug.
Pharmacodynamics
- It refers to the relationship between the drug
concentration at the site of action (receptor) and
pharmacologic response, including biochemical and
physiologic effects that influence the interaction of drug
with the receptor.
- What the drug does to the body
Toxicokinetics
- Application of pharmacokinetic principles to the design,
conduct and interpretation of drug safety evaluation
studies and in validating dose-related exposure in - Dissolution
animals.

Clinical Toxicology 2. Absorption

- The study of adverse effects of drugs and toxic - Process of uptake from the site of administration into
substances (poisons) in the body. the systemic circulation.

Pharmacokinetics Factors related to drug absorption

- Is the science of the kinetics of drug absorption, 1. Physicochemical properties of the drug
distribution and elimination (metabolism and excretion) 2. Nature of drug product
- what does the body do to the drug 3.Anatomy & physiology of drug absorption site

NOTE: The study of pharmacokinetics involves both 3. Distribution

experimental and theoretical approaches. The
experimental aspect of pharmacokinetics involves the
development of biologic sampling techniques, analytical
methods for the measurement of drugs and metabolites,
and procedures that facilitate data collection and
manipulation. The theoretical aspect of
pharmacokinetics involves the development of
pharmacokinetic models that predict drug disposition
after drug administration. The application of statistics is
an integral part of pharmacokinetic studies. Statistical
methods are used for pharmacokinetic parameter
estimation and data interpretation ultimately for the
purpose of designing and predicting optimal dosing
regimens for individuals or groups of patients.
Ladmer System
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L – liberation
A – absorption
D – distribution
M – metabolism
E – excretion
R – response
T- Toxicity
LADMER system
*Elimination = Metabolism + Excretion
*Disposition= Distribution + Elimination
- The drug’s movement to various sites after entering
systemic circulation.
- It refers to the reversible transfer of a drug between the
blood and the extra vascular fluids and tissues of the
body (for example, fat, muscle, and brain tissue).
Factors affecting distribution
A. Factor affecting RATE of distribution
- Membrane permeability
- Blood perfusion - process of a body delivering blood to
a capillary bed in its biological tissue. The word is
derived from the French verb "perfuser" meaning to
"pour over or through."
B. Factors affecting EXTENT of distribution
- Lipid solubility
- Ionization
- Protein binding
4. Metabolism (Biotransformation)
- Involves the conversion of the administered drug into
another substance.
- Xenobiotics convert into form that are less active or
inactive, less toxic or non-toxic and water soluble easily
excreted form.
It can result in the formation of either an active or
inactive metabolite
Parent Compound Metabolite (Active & Inactive)

NOTE: The description of drug distribution and First Pass

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elimination is often termed drug disposition.
Characterization of drug disposition is an important - Hepatic first-pass effect may occur following P.O. and
prerequisite for determination or modification of dosing deep rectal administration.
regimens for individuals and groups of patients. - Routes which by-pass the GIT degradation and hepatic
metabolism:
1. Liberation (Drug Release) 1) IV
- Delivery of the active ingredient from a dosage form 2) Sublingual
into solution. 3) Buccal
- Rate-limiting step
- Disintegration Intensive FPE = Lower Bioavailability

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5. Excretion
- The removal of the intact drug
- The process whereby drugs or metabolites are
irreversibly transferred from internal to external
environment through renal or non-renal route.
Types of Excretion
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1) Renal excretion
2) Non renal excretion
- Biliary excretion.
- Pulmonary excretion.
- Salivary excretion.
- Mammary excretion.
- Skin / Dermal excretion.
- Gastrointestinal excretion.
- Genital excretion.
Requirements for Drug Molecules for Them to Be
Absorbed and Reach Intracellular Targets
1) Non-ionized/Non-polar
2) Small Molecular weight
3) In aqueous solution
Cell Membrane
- Major structures in cells, surrounding the entire cell and
acting as a boundary between the cell and the interstitial
fluid.
- Transcellular absorption is the process of drug
movement across a cell. Some polar molecules may not
be able to traverse the cell membrane but, instead, go
through gaps or tight junctions between cells, a process
known as paracellular drug absorption.
Theories Regarding Plasma Membrane
Lipid bilayer or unit membrane theory
- Originally proposed by American anatomist, physician
and biochemist  James David Robertson
- It 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.
Fluid mosaic model
- S.J. Singer and G.L. Nicolson
GSDMSFI | BS Pharmacy 3
- According to this model, the cell membrane consists of
globular proteins embedded in a dynamic fluid, lipid
bilayer matrix. These proteins provide a pathway for the
selective transfer of certain polar molecules and charged
ions through the lipid barrier.
- “protein icebergs in an oily sea”
Cell Membrane Function
A semi-permeable partition that acts as selective barrier
for the passage of molecules:
- water
- some selected small molecules
- lipid-soluble molecules
Water, some selected small molecules, and lipid-soluble
molecules pass through such membranes, whereas
highly charged molecules and large molecules, such as
proteins and protein-bound drugs, do not.
Cell Membrane Characteristics
- Generally thin, approximately 70 to 100 Å in thickness
- Composed primarily of phospholipids
Modes of Drug Transport
1. Passive diffusion
- The process by which molecules spontaneously diffuse
from a region of higher solute concentration to a region
of lower solute concentration
- Drugs must be small and should be lipid soluble for
transport across the bilipid layer.
- Non-energy requiring
- Driving force – concentration difference
- The major absorption process for most drugs (but it is
also the slowest)
2. Passive diffusion
- Osmosis: movement of solvent to the area of low
concentration to the area of high concentration.
- Factors affecting Passive diffusion can be explained by
Fick’s Law of Diffusion:
dQ (flux) = (C1-C2) (SA) (Diffusion coefficient)
dt (membrane thickness)
Factors affecting Passive Diffusion
Concentration difference
- The higher the difference between two
compartments, the higher rate of molecule
movement.
Surface Area
- The greater the surface area =  flux 3. Carrier-mediated transport
- Small intestines > Stomach a) Active transport
Diffusion Coefficient b) Facilitated diffusion
- Affected by Permeability barrier

1. Particle size = smaller particle size occupies greater

SA
2. High Lipid solubility = High Diffusion coefficient

Lipid solubility determinants:

1) Degree of dissociation of drug (ionization)
- Greater ratio of non-ionized= Flux ionized
drug
2) Lipid-water partition coefficient

Ionization

Many drugs are weak acids or weak bases and can exist
in either nonionized or ionized forms in equilibrium,
depending on the pH of the environment and their pKa
(the pH at which the molecule is 50% ionized and 50%
nonionized). Only the NONIONIZED (uncharged) form of
a drug crosses biomembranes.

- Ionized = Water soluble

- Non-ionized, non-polar = lipid soluble

The percentage of ionization is determined by the

HENDERSON – HASSELBALCH equation.

- For weak acids: pH-pKa = log [I]/[UI] Similar Properties

- For weak bases: pH-pKa = log [UI]/[I] 1) Selectivity / specificity
2) Subject to competition
- For weak acids: ph – pKa = log - drugs with higher affinity to the carrier displace
[ionized]/[nonionized] drugs of lower affinity from the carrier
- For weak bases: pH – pka = log 3) Subject to saturability
[nonionized]/[ionized] - Because of the limited number of carrier
molecules
Primary Principles - Saturation kinetics

Ionization increases renal clearance of drugs Drug permeation is dependent on:

- Only free, unbound drug is filtered. 1) Solubility
- Both ionized and nonionized forms of a drug are 2) Concentration gradient
filtered. 3) Surface area and vascularity
- Only nonionized forms undergo active secretion and
active or passive reabsorption. 5. Vesicular transport
- Ionized forms of drugs are “trapped” in the filtrate. - does not require drug to be in aqueous form
- Pinocytosis – cell drinking
Lipid water partition coefficient - Phagocytosis – cell eating
- Ratio of the concentration of a given drug dissolved in
Lipid (octanol) layer to the amount of the same drug 6. Long pair
dissolved in water. - Formation of neutral ion pair complexes with
endogenous materials
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- Absorbed by passive diffusion
7. Convective transport
- Passing through channels in the cell membrane (pores)
Measurement of Drug Concentrations
Biologic samples that can be used:
1) Milk
2) Saliva
3) Plasma
4) Urine
Sampling of Biologic Specimens
Invasive methods – include sampling blood, spinal fluid,
synovial fluid, tissue biopsy, or any biologic material that
requires parenteral or surgical intervention in the patient.
Non-invasive Methods – sampling of urine, saliva, feces,
expired air, or any biologic material that can be obtained
without parenteral or surgical intervention.
- Plasma perfuses all the tissues of the body, including
the cellular elements in the blood. Assuming that a drug
in the plasma is in dynamic equilibrium with the tissues,
then changes in the drug concentration in plasma will
reflect changes in tissue drug concentrations.
Plasma-Level Time Curve
- generated by obtaining the drug concentration in
plasma samples taken at various time intervals after a
drug product is administered.
1. MEC (Minimum Effective Concentration) – the
minimum concentration of the drug needed at the
receptors to produce the desired pharmacologic effect.
2. MTC (Minimum Toxic Concentration) – the drug
concentration needed to just barely produce a toxic
effect.
3. Onset Time – the time required for the drug to reach
MEC.
4. Duration of Action – the difference between the
onset time and the time before the drug to decline back
to MEC.
5. tmax (Time of peak plasma level) – the time of
maximum drug concentration in the plasma and is the
rough marker of average rate of drug absorption.
6. cmax (Peak plasma level) – maximum drug
concentration
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7. AUC (Area under the Curve) – related to the amount
of drug absorbed systematically.
8. Therapeutic Index/ Range - the ratio of the dose that
elicits a lethal response in 50 percent of treated
individuals (LD50) divided by the dose that elicits a
therapeutic response in 50 percent of the treated
individuals (TD50).
T.I. = LD50
ED50
< 2 = toxic drug (narrow TI)
> 2 = Safe
Drug Response Curve
- The interaction between drug and its receptor can be
described by a curve called as drug response curve
- Vertical axis there is response of drug
- Horizontal axis there is concentration of dose
- The magnitude of drug effect depends on drug
concentration at receptor site and this availability and
concentration of drug at receptor is determined by both
dose of drug administered and by drug pharmacokinetics
(ADME)
- When no drug is added then no effect is produced.
- When some drug is added then we get response
- By adding more drugs we get maximum response
- A time will reach on which adding more drug will not
cause increase in response because we have reached
to maximum effect
 EC50 - Is concentration of drug needed to get
half of the maximum effect
Two important properties of drug can be found by dose
response curve
 Efficacy
 Potency
Efficay and Potency
- Efficacy or Ability of a drug to elicit a response when it
interacts with a receptor
- Efficacy is dependent on;
 The number of drug-receptor complexes formed
 Efficiency of the coupling of receptor activation
to cellular responses.
- Maximal efficacy of a drug assumes that all receptors
are response will be observed.
- Maximal response (efficacy) is more important than
drug potency.
- A drug with greater efficacy is more therapeutically
beneficial than the one that is more potent.
Drug Concentration in Tissue
- Drug concentrations in tissue biopsies may not reflect
drug concentration in other tissues nor the drug
concentration in all parts of the tissue from which the
biopsy material was removed.
- The measurement of the drug concentration in tissue
biopsy material may be used to ascertain if the drug
reached the tissues and reached the proper
concentration within the tissue.
Drug Concentration in Urine and Feces
- Measurement of drug in urine is an indirect method to
ascertain the bioavailability of a drug. The rate and
extent of drug excreted in the urine reflects the rate and
extent of systemic drug absorption.
- Measurement of drug in feces may reflect drug that has
not been absorbed after an oral dose or may reflect drug
that has been expelled by biliary secretion after systemic
absorption.
Drug Concentration in Saliva
- Saliva drug concentrations have been reviewed for
many drugs for therapeutic drug monitoring (). Because
only free drug diffuses into the saliva, saliva drug levels
tend to approximate free drug rather than total plasma
drug concentration.
Forensic Drug Measurement
- Forensic science is the application of science to
personal injury, murder, and other legal proceedings.
Drug measurements in tissues obtained at autopsy or in
other bodily fluids such as saliva, urine, and blood may
be useful if a suspect or victim has taken an overdose of
a legal medication, has been poisoned, or has been
using drugs of abuse such as opiates (eg, heroin),
cocaine, or marijuana.
- These drugs may be eliminated rapidly, making it more
difficult to prove that the subject has been using drugs of
abuse
Significance of Measuring Plasma Drug
Concentration
- Because most of the tissue cells are richly perfused
with tissue fluids or plasma, measuring the plasma drug
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level is a responsive method of monitoring the course of
therapy.
- Monitoring the concentration of drugs in the blood or
plasma ascertains that the calculated dose actually
delivers the plasma level required for therapeutic effect.
- Pharmacokinetic models allow more accurate
interpretation of the relationship between plasma drug
levels and pharmacologic response.
In the absence of pharmacokinetic information, plasma
drug levels are relatively useless for dosage adjustment.
- Monitoring of plasma drug concentrations allows for the
adjustment of the drug dosage in order to individualize
and optimize therapeutic drug regimens.
- In many cases, the pharmacodynamic response to the
drug may be more important to measure than just the
plasma drug concentration.
- For drugs that act irreversibly at the receptor site,
plasma drug concentrations may not accurately predict
pharmacodynamic response.
Basic Pharmacokinetics and Pharmacokinetic
Models
- Drugs are in a dynamic state within the body as they
move between tissues and fluids, bind with plasma or
cellular components, or are metabolized. The biologic
nature of drug distribution and disposition is complex,
and drug events often happen simultaneously. Yet such
factors must be considered when designing drug therapy
regimens. The inherent and infinite complexity of these
events requires the use of mathematical models and
statistics to estimate drug dosing and to predict the time
course of drug efficacy for a given dose.
- A model is a hypothesis using mathematical terms to
describe quantitative relationships concisely. The
predictive capability of a model lies in the proper
selection and development of mathematical function(s)
that parameterize the essential factors governing the
kinetic process.
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.
- 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 toxicologic activity
5. Evaluate differences in the rate or extent of
availability between formulations
(bioequivalence)
6. Describe how changes in physiology or disease
affect the absorption, distribution, or elimination
of the drug
7. Explain drug interactions
Compartment Models
- Physiologic pharmacokinetic models are frequently
used in describing drug distribution in animals, because
tissue samples are easily available for assay. On the
other hand, tissue samples are often not available for
human subjects, so most physiological models assume
an average set of blood flow for individual subjects.
- In contrast, because of the vast complexity of the body,
drug kinetics in the body are frequently simplified to be
represented by one or more tanks, or compartments,
that communicate reversibly with each other. A
compartment is not a real physiologic or anatomic region
but is considered as a tissue or group of tissues that
have similar blood flow and drug affinity. Within each
compartment, the drug is considered to be uniformly
distributed.
Mammillary Model
- The mammillary model is the most common
compartment model used in pharmacokinetics. The
mammillary model is a strongly connected system,
because one can estimate the amount of drug in any
compartment of the system after drug is introduced into
a given compartment.
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.
Physiologic Pharmacokinetic Model (Flow Model)
- Physiologic pharmacokinetic models, also known as
GSDMSFI | BS Pharmacy 3
blood flow or perfusion models, are pharmacokinetic
models based on known anatomic and physiologic data.
- The model would potentially predict realistic tissue drug
concentrations, which the two-compartment model fails
to do.
Major differences are described:
- 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 taken into account in physiologic
pharmacokinetic models.
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.
The number of tissue compartments in a perfusion
model varies with the drug. Typically, the tissues or
organs that have no drug penetration are excluded from
consideration. Thus, such organs as the brain, the
bones, and other parts of the central nervous system are
often excluded, as most drugs have little penetration into
these organs. To describe each organ separately with a
differential equation would make the model very complex
and mathematically difficult. A simpler but equally good
approach is to group all the tissues with similar blood
perfusion properties into a single compartment.
MATHEMATICAL FUNDAMENTAL IN
PHARMACOKINETICS
- Pharmacokinetic models consider drugs in the body to
be in the dynamic state. Calculus is an important
mathematical tool for analyzing drug movement
quantitatively.
*Note: Differential Equations are used to relate the
concentration of drugs in various body organs over time.
Integrated equation is frequently used to model the
cumulative therapeutic or toxic responses of drug in the
body.
Pharmacokinetics
- Pharmacokinetics is currently defined as the study of
the time course of drug absorption, distribution,
metabolism, and excretion.
 Clinical pharmacokinetics

- is the application of pharmacokinetic principles to the Rates and orders of reaction

safe and effective therapeutic management of drugs in
an individual patient. Rate
*Note: Primary goals of clinical pharmacokinetics -The rate of a chemical reaction of process is the
include enhancing efficacy and decreasing toxicity of a velocity with which the reaction occurs.
patient’s drug therapy. The development of strong
correlations between drug concentrations and their Rate Constant
pharmacologic responses has enabled clinicians to -The order of a reaction refers to the way in which the
apply pharmacokinetic principles to actual patient concentration of drug or reactants influences the rate of
situations. Kinetic homogeneity describes the predictable a chemical reaction or process.
relationship between plasma drug concentration and
concentration at the receptor site where a given drug
produces its therapeutic effect (Figure 1-2). Changes in
the plasma drug concentration reflect changes in drug
concentrations at the receptor site, as well as in other
tissues. As the concentration of drug in plasma
increases, the concentration of drug in most tissues will
increase proportionally.

Unit for Expressing Blood Concentration

- Drug concentrations or drug levels should be

expressed as mass/volume. The expressions mcg/mL,
g/mL, and mg/L are equivalent and are commonly
reported in the literature. Drug concentrations may also
be reported as mg% or mg/dL, both of which indicate
milligrams of drug per 100 mL (deciliter). The accurate
interconversion of units is often necessary to prevent Units in Pharmacokinetics
confusion and misinterpretation.
*Note: Various units have been used in pharmacology, Two Important Pharmacokinetic Order
toxicology, and the clinical laboratory to express drug 1. Zero-Order Kinetics
concentrations in blood, plasma, or serum. 2. First Order Kinetics
Practical Focus
Determination of Order
-Significant differences in plasma drug concentrations
may result if the dose is based on a different method. Substitution Method
Drug concentrations may also be different if a dose is - When the equation is found in which the calculated k
injected rapidly versus infused over a period of time. values remain constant within the limits of experimental
variation, the reaction if considered to be of that order.
-Most potent drugs are dosed precisely for the individual
patient, and the body weight of the patient should be Graphic method
known. - If a straight line results when concentration is plotted
against t the reaction is zero order. The reaction is first
-For drugs with a narrow therapeutic index and potential order if the graph yields a nonlinear.
for side effects, dosing based on body surface is
common.

Chemical kinetics

-branch of chemistry which addresses the question:

"how fast do reactions go?"

GSDMSFI | BS Pharmacy 3
 Zero Order
Zero- Order First Order
Reaction Reaction - One that proceeds over time (t) independent
from the concentration of the drug (c).
Effect of time on Zero-order rate is First order rate will
rate constant with change with - Does not consider the remaining concentration
respect to time respect to time as of drug and excrete the drug in a constant
concentration manner.
changes.
-
Effect of time on Rate constant with Rate constant Ex:
rate constant respect to time remains constant
changes as the with respect to
concentration time
changes
Drug concentration Drug Drug concentration
versus time- concentrations decline nonlinearly
plotted on decline linearly for for a first-order rate
rectangular a zero- order rate process.
coordinates process
Drug Drug Drug concentration
Concentration concentrations decline linearly for
versus time plotted decline nonlinearly a single first-order
on a semi for a zero-order rate process.
logarithmic graph rate process

Comparison of Zero and First Order Reaction

Aspirin, Phenytoin, Ethanol

Time Zero-Order First Order

Concentration Concentration
(mg/mL) (mg/mL)
0 100 100
1 80 50 *Note: Negative signs for the rat indicates that the
concentration of the drug decrease overtime
2 60 25
3 50 12.5 Formula for Zero Order

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 First Order

- A reaction is first order if the rate of the reaction varies

directly with the concentration of the reactant. If the
reaction doubles, the rate of reaction also doubles.
- The rate of reaction is dependent on the remaining
concentration.

Formula of First Order

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 2.303
2.303

GSDMSFI | BS Pharmacy 3