Unit 1: Introduction

Thursday, November 20, 2014

10:27 PM

Biopharmaceutics
Science of dosage form design
Science that deals between interrelationship of dosage forms, route of administration,
and physicochemical properties on the rate and extent of systemic absorption
(bioavailability) in living organisms
Incorrect bioavailability leads to sub-therapeutic or toxic effects.
Physicochemical properties of drugs
Ex: pKa, partition coefficient, polymorphism
Pharmacokinetics
Science that deals with kinetics (movement) of drugs
Absorption, distribution, metabolism, excretion
Goal of biopharmaceutical studies
Develop dosage form that will provide consistent bioavailability at a desirable rate
Applications of pharmacokinetics
Bioavailability measurements
Effects of physiological and pathological conditions on drug disposition and absorption
Dosage adjustment of drugs in disease states, if and when necessary
Correlation of pharmacological responses with administered doses
Evaluation of drug interactions
Clinical prediction: using pharmacokinetic parameters to individualize the drug dosing
regimen and thus provide the most effective drug therapy
Definition
Biopharmaceutics
Liberation
In vivo
In vitro
Absorption
Pharmacokinetics
Absorption
Distribution
Metabolism
Elimination
Pharmacodynamics
Metabolism
Elimination
Response
Fate of drugs
LADMERT of active ingredient of drug
What happens to the active ingredient after it has been administered
LADMER System
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LADMER System
Development of new active compounds, analogs and derivatives
Development of dosage forms with desired release characteristics
Determination of pharmacokinetic parameters and pharmacokinetic drug product profiles
Determination and evaluation of bioavailability
Selection of the most appropriate route of administration
Determination of effective dose sizes
Adjustment of dosage regimen to achieve a desired therapeutic concentration of drug in
the body
Highly-perfused organ
Organ with lots of blood flow
Heart, liver, intestine, brain
Review of ADME Processes
ADME is an acronym representing the pharmacokinetic processes of absorption,
distribution, metabolism and elimination
Absorption
The process by which a drug proceeds from the site of administration to the site of
measurement (usually blood, plasma or serum)
Distribution
The process of reversible transfer of drug to and from the site of measurement
(usually blood or plasma)
Any drug that leaves the site of measurement and does not return had undergone
elimination
The rate and extent of drug distribution is determined by:
How well the tissues and/or organs are perfused with blood
The binding of drug to plasma proteins and tissue compartments
The permeability of tissue membranes to the drug molecule
Metabolism
The process of conversion of one chemical species to another chemical species
Usually, metabolites will possess little or none of the activity of the parent drug.
However, there are exceptions. Some examples of drugs with therapeutically active
metabolites are:
Procainamide ----> N-acetyl pracainamide
Propranolol ----> 4-hydroxypropranolol
Diazepam ----> desmethyldiazepam
Aspirin (acetylsalicylic acid) ----(metabolic rate constant, Km)----> salicylic acid ---Km----> gentisic acid, salicylglucoronide, salicyluric acid (all are inactive)
Elimination
The irreversible loss of drugs from the site following measurement (blood, serum,
plasma)
Elimination of drugs occur by one or both:
Metabolism
Excretion
Elimination vs. Excretion
Elimination = drug undergoes chemical change
Excretion = no chemical change occurs
Excretion
The irreversible loss of a drug in a chemically unchanged or unaltered form
Disposition
The distinction between elimination and distribution is often difficult
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 The distinction between elimination and distribution is often difficult

When such a distinction is either not desired or it is difficult to obtain, disposition is
the term used
It is defined as all the processes that occur subsequent to the absorption of the
drug, hence, the components of the disposition phase are distribution and
elimination
Routes of administration
Enteral
Major
Parenteral
Inhalational
Intranasal
Intrathecal/intraventricular
Topical
Transdermal
Rectal

Enteral
Oral
Easily administered
Limit systemic infections
Toxicities/overdose may be overcome
Absorption is complicated
Affected by food
Sublingual
Rapid administration
Convenient
Low incidence of infection
Avoidance of harsh GI environment
Avoidance of first-pass metabolism
Parenteral
Intravascular
Avoids GI tract and first-pass metabolism
Rapid effect
Maximal degree of control
High risk for systemic infection
Increased risk for adverse or untoward effects
Intramuscular (subdivided into intravenous and intraarterial)
Rate of absorption is adjustable
Subcutaneous
Minimal risk associated with IV route
Administration of solid drugs and mechanical devices
Others
Inhalational
Rapid delivery
Only for gases/aerosols
Effective for respiratory diseases
Intranasal (Ex: Desmopressin, for diabetes insepidus; Salmon calcitonin, Muconase)
Local and systemic effects
Intrathecal/intraventricular
Anesthesia
CNS diseases
Topical
Local effect
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 Local effect
Transdermal
Systemic effects
Absorption varies markedly
Rectal
Avoidance of the harsh GI environment
Useful for drugs that induce vomiting
Indicated for patients unable to take oral meds

The Hepatic/Portal System

First-pass effect
Metabolism of drugs by the liver before reaching the systemic circulation
Reason for the difference in the half-life of some drugs when given IV & PO
Explains quantitative and qualitative differences in the metabolism of the same drug
following IV and PO administration
Is not only observed upon PO administration but also upon deep rectal administration
The importance of the first-pass effect depends on the metabolic capacity for the
particular drug, rate of metabolism and rate of absorption
If the amount of drug administered is small, but capacity and rate of metabolism are high,
a large fraction of the drug may be metabolized, reducing the extent of bioavailability
With increasing dose sizes first-pass metabolism may become saturated, thus increasing
the extent of bioavailability
Bioavailability
The bioavailability of a drug is the fraction of the administered dose that reaches the
systemic circulation
Bioavailability is 100% in the case of IV administration
After administration by other routes, bioavailability is generally reduced by:
1. Incomplete absorption
2. First-pass metabolism
3. Distribution into other tissues that occurs before the drug enters the systemic
circulation
Two major factors affecting bioavailability
1. Formulation factors
Ex: types and concentration of excipients, particle size of active ingredient,
crystalline/amorphous, hydrous/anhydrous, polymorphic nature
2. Physiological factors
Ex: disease sates, gastric emptying, intestinal motility, changes in GI pH,
changes in intestinal wall
Even for drugs with equal bioavailabilities, entry into the systemic circulation occurs over
varying periods of time, depending on the drug formulation and other factors
To account for such factors, the concentration appearing in the plasma is integrated over
time to obtain an integrated total area under the plasma concentration curve

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Area under the curve (AUC)

Reflects the actual body exposure to drug after administration of a dose of the drug
Is dependent on the rate of elimination of the drug from the body and the dose
administered
The total amount of drug eliminated by the body may be assessed by adding up or
integrating the amounts eliminated in each time interval, from time zero (time of the
administration of the drug) to infinite time
This total amount corresponds to the fraction of the dose administered that reaches the
systemic circulation
The AUC is directly proportional to the dose when the drug follows linear kinetics
The AUC is inversely proportional to the clearance of the drug
That is, the higher the clearance, the less time the drug spends in the systemic
circulation and the faster the decline in the plasma drug concentration
Therefore, in such situations, the body exposure to the drug and the area under the
concentration-time curve are smaller
Therapeutic Window
The therapeutic window is the safe "opening" between the minimum therapeutic
concentration and the minimum toxic concentration of a drug
The concept is used to determine the range of plasma levels that is acceptable when
designing a dosage regimen
Thus the minimum effective concentration will usually determine the desired trough levels
of a drug given intermittently, while the minimum toxic concentration determines the
permissible peak plasma concentration

Receptors
Binding sites of ligands (drugs)
Made of proteins
Specific location of receptors in the cell:
Cell membrane
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Cell membrane
Nucleus
Mitochondria
Endoplasmic reticulum (ER)

Structure-specific
Pharmacologic action is dependent on chemical structure of drug
Four prerequisites of drugs that can bind to receptors:
Chemical reactivity
Presence of functional groups
Electronic distribution
.
Four drug-receptor theories:
Hypothesis of Clark
Hypothesis of
ns and Stephenson
Hypothesis of Paton
Lock and Key Hypothesis
What can you conclude based on the four hypotheses?
In order for drugs to have an effect, it should have an affinity for the receptor. It should
have intrinsic activity.

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