Lecture 1

Biopharmaceutics: a subject that deals with the fate of drug

after administration into a living body, this fate express the net
result of a medicine undergoes after administration through
the process ADME.
Science that deals with interrelationship between drug product
and biological system in order to produce Drug action.
This ADME process encounter some factors :
 Physiochemical properties of drug.
 Pharmacological factors
 Pharmacodynamics factors
Pharmacokinetics: the rate of changes occurring in the
medicine or drig following ADME processes with time as the
drug travels one or more compartments.
Pharmacodynamics: describes the interrelationship between
drug concentration at the site of action and drug response.

Post drug administration events

1. Pharmaceutical Phase : disintegration, Dissolution
2. Pharmaceutical availability
3. Pharmacodynamics availability and phase
(bioavailability)
 Bioequivalent: same drug, different formulation but
same rate ands extent of absorption
 Chemical equivalent: When derivatives give the
same reaction as the parent drug
 Therapeutic equivalent: therapeutic effect same
though form is different
 Influence of factors on bioavailability:
 Pharmaceutical factors
 routes of administration:
 Dosage form
 Form of drug: example: ampiciline hydrated form
rapid dissolution than Anhydrous form
 Polymorphic state: melting point solubility
density. More stable form is recommended
 Drug dissolution: Noyes Whitney law: the rate of
dissolution is Proportional to the surface area of
solid particles, it is directly proportional to the
concentration of the solid between the surface
and the bulk and it is inversely proportional to
the thickness of the interface or thickness of the
layer line between the solid and liquid interface,
it is proportional to the volume of the media.
 Solubility: Polar salute dissolves in polar solvent .
Hydrophilic drugs are rapidly soluble in
hydrophilic are water based environment
example blood plasma Amniotic fluid , lacrimal
fluid. Semi polar molecule are readily permeable
 PH:
 Lipid water partition coefficient: distribution of
molecule between polar and nonpolar phase.

Lecture 2
 Pharmacological phase:
  Absorption: biological membrane penetration.
Biological membrane at the barrier of our
organ which can be single or multi layered.
penetration is actually diffusion.
Fick's first law of diffusion: The rate of transfer of
molecules is proportional to the surface area and
concentration, inversely proportional to thickness of
the Membrane.
Type of diffusion:
Passive diffusion: diffusion of molecules through
membrane without energy expenditure
 Aquous diffusion or poor convective
transportation: water helps diffusion cellular
lining contains pores which are filled with
water polar molecules are diffused through
these water channels. Factors that effect
aqueous diffusion: Molecular size, polarity,
membrane potential.
 Lipid diffusion: lipid bilayer membraneIs this
the way for hydrophobic drugs
Active transportation: carrier mediated or enzyme
mediated transportation. lower to high region. Drugs
combined with carrier protein and form a complex with
covalent bond, carriers release the drug and return for
another drug this process exhibit situation phenomena.
Facilitated diffusion: mix of passive and active diffusion
higher to lower concentration exhibit saturation
phenomena
Ion pair transportation: electrolyte drugs are transported
by this way PK dependent they are extremely pola. So
 here Strong polar drug becomes ionized and Bears with
opposite charges and becomes neutralize these
neutralized molecule penetrates easily temple propanol,
quinine propanol when given with oleic acid it forms a
pair and diffuse rapidly.
vesicular transportation: pinocytosis and phagocytosis
process Dissolves drug and the drug goes to the site of
action. this is a selective process. example polio vaccine
absorbs via pinocytosis. Insulin is absorbed by
phagocytosis.

Lecture number 3
Biological factors that affect absorption:
 Structure and composition of biological membrane: semi
permeable in nature. taking this can alter permeability.
Single layer, multi layer membrane. Phospholipid bilayer
which is amphoteric; hydrophilic head and hydrophobic
tail. Integral proteinvery fair of protein, peripheral protein
and I on channel.
 Influence of GT: oral administered drug: saliva makes
the drug slippery, esophageal sphincter prevents acid
reflux, Stomach HCL solubilized drug, then drag goes to
dude in AM by peristalsis movement. Gastric emptying
time depends on food nature, Fatty acid and highly
densed food has more stomach emptying time that alters
the absorption time.
 Lecture 4
Stereogenic prodrugs are destabilized by hydrolysis as a
result reduced bioavailability.
Effect of small intestine on bio availability: Major site of
absorptionBecause folding of intestinal lining he increases the
surface area where filament like process turn which is called
villi, are situated these villas increase surface area.Small
intestine has more blood flow than stomach and pH level is 7.5
which is neutral and Helps nonionic drug to permit through the
membrane
Large intestine no villino microvilli, less absorption. Some
specific drugs are absorbed well from in this time like to file in,
metoprolol Q filing they give sustained release doses. mucosal
flora has some engine that helps the drug to be absorbed
example lectu lays helps propanil
Some phenomena that effect drug absorption:
 gastric emptying time
 gastric motility
 residence time
 gastric pH
 gastric secretion
gastric emptying time:
Rapid gastric emptying time: In case of rapid onset of action
example sedatives, Enteric coated tablets. Penicillin
Some drugs are absorbed well in the distal portion of small
intestine example vitamin B12
Delayed gastric emptying time: griseofulvin, absorbs well with
food.
Some drugs irritate gastric mucosa example aspirin
phenylbutazone
Vitamin C should be in the small intestine for prolonged time
for better absorption.
Factors effecting gastric emptying time:
 Volume of Meal: follows first order reaction connetics
 Composition of meal: Fatty foods increase gastric
emptying time because they are emulsified by bile
secretion and form a complex.
 Viscosity of the meal: liquid food rapid emptying time,
solid food delayed.
 Temperature of the meal: food and body temperature
difference বেশি হইলে gastric emptying time delayed হয়।
pH of the GIT: Gastric emptying time delays in acidic pH, and
promoted in alkaline pH. Molecular weight of biocompatible
acid Controls gastric emptying time hi molecular weight
decrease emptying time. Biocompatible sodium bicarbonate
promotes emptying rate. Dilute concentration is more effective
Electrolyte and osmotic pressure: low salt concentration
increases emptying rate
Body posture: when standing up downhill phenomenal works
which helps gastric emptying
Emotional state: stressful condition anxiety increases motility.
Sadness decreases motility
Exercise: vigorous exercise decreases emptying
Disease state: diabetes, hyperthyroidism, gastric
ulcerdecreases emptying rate but doodle alser increases
emptying great
Nature of the drug: and the seed, narcotics, analgesics, NT
cholinergic, tricyclic antidepressant decreases emptying rate.
Metro kuklos promide, domperidone, she supplied promote
gastric emptying rate.

Small intestine his main set of drug absorption which has larger
surface area.
1. Transit time in different part of the intestine –
Duodenum 5 min
Jejunum 2 hrs
Ileum 3-6 hrs
Cecum 30 min – 1 hr
Colon 6-12 hrs
Delayed transit time: increases bioavailability because more
absorption occurs.
Example: SRDF, Enteric coated, several vit B
Rapid intestinal transit time: laxatives
Factors effecting transit time :
1. Food: retarded transit time. Digestive enzymes help
increasing transit time
2. Drug: anticholinergic drug decreases, laxative,
metoclopramide increases time.
3. Diseases : 3 type diseases –
 GI disease: pathogenic conditions like diarrhea,
constipation affect absorption pattern, motility,
leading to reduced bioavailability.
 Cardiovascular : can inhibit normal functioning
parameters. Can cause intestinal edema, reduced
 blood flow in GI, altered Gastric emptying time pH,
microbial flora change.
Hepatic : hampers fast pass metabolism. Example:
propanolol.
Effect of pH: pH affects some parameters: disintegration,
dissolution, absorption, stability.
1. Disintegration of enteric coated tablet affected by pH.
Others don’t
2. Dissolution is applicable for weakly acidic or weakly basic,
affects Oral bioavailability. Acidic drug- undissociated in
acidic environment. As a result, better absorption. But in
alkaline environment it is ionized and become difficult to
pass lipid bilayer membrane. Active transportation is
required which is selective and saturated phenomena
designed.
3. Stability : pH hampers drug stability. Example : penicillin
G, erythromycine degrades in acidic media.
Enzyme: proteolytic enzyme of intestine degrades drug with
polypeptide linkage or proteinacious drug. Example insulin,
oxytocin, vasopressin
Interaction with GI contents:
1. Food drug interaction : delayed absorption : aspiring,
paracetamol, diclofenac, digoxin. Decreased absorption :
penicillin, erythro, levodopa, iron. Increased absorption :
griseofulvin, diazepum, water soluble Vit. Not affected:
methyl dopa, propylthiouracil.
2. Drug drug interaction :
 Physiochemical drug drug interaction :
absorption : antidiarrheal with absorbent (kaoline,
pectin) interfere with other drugs ( promazine,
vencomycin). Result, retarded or no absorption.
 Complexion: fe, Mg, Al, Ca antacids bind with
tetracycline and form unabsorbable complex. Result,
no absorption.
pH change: NaHCO3 in antacids changes pH to alkalies,
as a result Tetracycline absorption reduces.
 Physiological drug drug: gastric emptying time
alteration.
 First pass metabolism : also called pre systemic
metabolism because drug is metabolized before
entering into the systemic circulation. Decreases
absorption. Four type of enzymes are responsible. They
are
Luminal enzyme: Found in gut fluid and intestinal
pancreatic secretion. Example: chloramphenicol
palmitate is hydrolyzed and activated; peptide is
engine breaks amide linkage which inactivate a drug
example protein drug
Gut wall enzymes: found in stomach intestine and
example alcohol dehydrogenase inactivate ethanol
Bacterial engine: found in colonic region which is
microflora can activate drugs or make it toxic
example: sulphasalazine becomes hydrolyzed and
produce sulfapyridine and five amino salicylic acid.
Hepatic enzyme: first fast metabolism occurs.
Example: Isoprinosine, propanol

Lecture 6

factors of non integral route which affected by availability of a

drug:
There is no GI influence in non enteral route or extravascular
route.
Non invasive route:
1. Sublingual and buccal route: Extremely vascularized, thin
lining helps drug absorbed rapidly .
Advantage: no first pass effect; no enzyme and particular
pH

Buccal route : between cheek and gum the drug is

pleased then it gradually dissolves and passive diffusion
occurs.
Advantage: Same as sublingual
factors affecting sublingual Buckle root:
 Lipophilicity of the drag
 Celery secretion and pH 6
 Binding extension of drug in oral mucosa: List
absorption because of binding
 Storage facility: Tablet binds with :
 Oral epithelium thickness
An example: antipyretic drug, antihypertensive, steroidal drug
2. Rectal administration: factor Considered preparing rectal
administration dose
 Base of formulation: Base should have affinity for
formulation but not that strong because rectal fluid has
to subside Drug from the base. Polyethylene glycol
causes irritation and then defecation
 Fecal amount: Drug action subsided
 PH: around 8, an ionized form adverbs readily
 Example: painkiller, ultra short acting barbiturates
3. Topical administration: local action, transdermal
preparation. Trans dermal preparation factors:
  thickness of the membrane,
 presence of hair follicle,
 Trauma,
 Hydration of the skin,
 Age : infant sensitive skin
 humidity(Increases penetration and absorption)
and temperature
 Permission enhancer: dimethyl sulfoxide,
propylene glycol increases absorption
 Chronic uses of cortisol and salicylic acid enhances
permission
4. Intravascular administration: three places: deltoid, thigh,
Hip.
 Bioavailability depends on lipid solubility or even
isation
 Molecule size of drugs: small Or ionic drugs go
through the port but macromolecule first go to
lymphatic system
 Volume of injection and drug concentration
 PH and viscosity of the injection vehicle
5. Pulmonary administration: inhalation or aerosol puff.
Surface area of alveoli large so that permeability is high
perfusion rate is high.
Example: bronchodilators, anti the inflammatory steroids , anti
allergic
Factors affecting pulmonary administration:
 Particle size of aerosol form: more than 10 microns might
stuck in upper mucosa but smaller than.6 Micron my exile
while breathing
 Patient’s condition
 Drug condition: volatile or gaseous
 Droplet size:
6. intranasal administration: peptide or protein drug
specially anti diabetic drugs are considered
Advantages: no fast pass metabolism, stable in gastric
media, no pre systemic enzyme.
Factors affecting intranasal bio ability:
 Molecular weight: 200 dash 1000 Dalton
 Lipophilicity
 Nature of the drug
 Mucous membrane layer
7. Intraocular administration: drug given in optic cavity and
cul de SAC
 Structure of eye :
 চোখের ধারণ ক্ষমতা ৭-১০ মাইক্রন। more than two drops
will not be effective
 PH of lacrimal fluid 7.4
 Lysosomal enzyme might damage the drug
 Non irritable drug

8. Vaginal administration:
 PH of vaginal secretion
 Microorganisms of vaginal secretion
 Conveniency in use
 Distribution

Double peak effect:

Its a phenomena occurs in fasting conditions,in which the
plasma concentration shows a peak with a relation of time and
then declines and again shows the peak.
3 reasons are behind it:
1. wrong formulation 2.Irregular emptying 3.drug accumulation
in gallbladder

Distribution definition: It is process in which a reversible

transfer of drug between blood and other tissues of the body
occurs or simply with extracellular fluids.
MOA:
Distribution occurs by passive diffusion in which there is a
concentration gradient between blood and extracellular
fluids,thus drugs diffuse from higher to lower concentration. It
follows flicks low.
Ficks law: the rate of diffusion is proportional to the surface
area of the membrane,concentration and inversely
proportional to the thickness of the membrane.
the Wagner-Nelson method has been used to describe
precisely the absorption kinetics of orally
administered drugs and its reliability is
independent of the nature of gastric emptying
Why distribution is important?
Distribution makes the drugs available to the site of action and
there it influences
1.Onset of action 2.intensity of action 3.duration of action

Distribution is unequal in different compartments due to some

factors :
1. Tissue permeability and drug penetration
(sub-factors of drug: a.molecular size, b.degree of
ionization c.partition co-efficient)
Sub-factor -physiologic- barriers

 Size less than 500-600 dalton easy penetration

 Large molecules needs carrier mediated diffusion
B. Unionized drug is more permeable
The more ionized the more lipophilic and less permeation
Acidic drugs in acidic medium are not ionized so good
diffusion,same for basic for basic.

(barbiturate acidic drugs and in case of poisoning,use of the

NaHCO3 makes the medium basic and the barbiturate becomes
ionized and distribution stops and poisoning agents pass out
along with urine)

C. Partion co-efficent: two phase present in fluid and

membrane, the Co-efficient changes due to ionization.
(same P.C.E among phenobarbitol and salicylic acid, but
phonobarbitol is moreunionized so fastly distribute)
For polar drug: effective partition co-efficient is main indicator
.the higher effective partition co efficient the higher rate of
distribution. (thiopental is less ionized than salicylic acid and
thus distribution is higher and can cross BBB more than
salicylic acid)

Sub -factor -physiologic barrier:

 Simple capping endothelial barrier:capillary membrane
 Simple cell barrier: cell membrane-small size(50 DA) easy
penetration, lipophilic and size 50-600da, passive diffusion,
larger than that carrier mediated diffusion
 BBB: made with astrocytes,pericytes and capillary
endothelium. Highly selective.free access of drug is
restricted. Extremely lipophilic drugs can cross BBB.ex-
thiopental
Normally drugs can’t cross BBB but there are 3 ways to solve
that
A)using permission enhancer ,ex-DMSO-dimethyl sulfoxide
B) Disruppting BBB integrity by using osmotic infuencers,ex-
manitol(decreases the tightness in BBB)
C) Using redox system mediated by dihydropyridine
 Blood cerebrospinal fluid barrier: made with chorodi
plexus,junctions are slightly open so drugs can move well
 Placental barrier:lower molecular size and high lipophilicity
can cross placenta,ex-ethanol,barbiturate,anti biotics
 Blood testis barrier: made with sertoli cells,tight junctions
2. Tissue,organ size and drug perfusion rate
Apparent volume of distribution:apparent volume in the body
fluids in which the drug is dissolved.
Liver kidney brain highly perfused with blood,
moderate:skin,poor:fat,bone. Thiopental goes to brain easily
but works short period of time but in fat goes slowly and works
for longer period of time.

3. Extent of drug binding to the cellular and tissue

compartments
Two types of bindings one-with blood compartments two-
extravascular compartments
Protein binding-basically bonds with blood plasma
proteins.weak force vaan dar wals,ionic etc.reversible binding.
Sometime creates complexes which can’t pass through.
Irreversible bind creates toxicity-chroloform in liver
serum albumin has sites of binding

one-for warfarin (most drugs binds here- NSAIDs-

naproxane,sulfonamides- sulfamethoxine)
Two- diazepam binding site
Three-digitoxin
four-tamoxifen
Binding to lipoprotein:
Drugs have to be lipid containing

Binding to globulin:alpha 1-cortisone ,prednisone

Alpha 2- vitamin KEDA
Beta 1 -ferrous ion
Bets 2 - corticosteroids
Gamma globulin-immune system

Binding to RBC= Three things haemoglobin,cabonic anhydrage,

cell membrane can binds drugs

Tissue bindings: increase Apparent volume of distribution and

localized effects. If for long period then toxicity.
4. Other: a)patients age b)co-existing diseases c) other drug
therapy

Trapezoidal rules:
It is a rule that evaluates area under the curves by dividing the
total area into smaller trapezoids rather than rectangles.

Model:

Model is a mathematical description\ expression of a biological

system is used to express quantitative relationship
Compartment is a group a tissues with similar blood flow.

Pharmacokinetic models are hypothetical structures to describe

the fate of a drug in a biological system after administration.
Pharmacokintic models are those model which provide concise
means of expressing mathematically or quantatively the time
course of drug throughout the body and complete meaning full
pharmacokinetic parameters.

Significance of model: they are cute to see and sexy ,isn’t it

right tayef?
1. helps to characterize drugs behaviour
2. Helps us to determine drugs concentration in different body
fluids
3. Helps to predict multiple dose curve
4. Helps to calculate optimum dosage regimen
5. Evaluating bioequivalence among different formulation
6. Find out possible accumulation of drug in different organs

Types

1. compartment model(Caternary ,mamilary)

2. Non compartment model(Auc,mrt,MaT,Cl)
3. Physiologic models
Compartment model: to determine pharmacokinetic
parameters of absorption phenomena
1. One compartment open model: The one-compartment
open model is the simplest way to describe the process of
drug distribution and elimination in the body. This model
assumes that the drug can enter or leave the body (ie, the
model is “open”), and the entire body acts like a single,
uniform compartment.
2. Multi compartment model

Study protocol and bio-equivalence

The rate and extend of a drug that reaches the sytemic

circulation from a drug product.
Comparative study between standard drug and the test
formula on the basis of safety and efficacy, if similar then bio-
equivalent.

Relative bio-equivalence: rational between a recognized drug

and test drug

Absolute bio :
Ratio between bio-availability of a drug given oral and
intravenous.

When to test bio-availability test:

1. for new drug
2. Various formulation of same drug
3. Administration in different route
4. Approved drug er new formulation development

Lecture 15
Bioavailability and Bio equivalence
Parallel Design : The aim of experimental designs is to minimize
the experimental variables and to avoid a bias. In a parallel
design, two formulations are administered to two groups of
volunteers.
To avoid a bias, formulations may be administered randomly to
the volunteers. The major disadvantage of this design is that
the inter-subject variation is not being corrected. It has been
proved beyond doubt that most of the times inter-subject
variation is greater than the variation between any
formulations. Therefore, a cross-over design is preferred in
bioavailability/bioequivalence trials to avoid influence of a
inter-subject variation.
Drug products
Test products: Test product(s) may be new drug formulations
developed by a pharmaceutical technologist or new dosage
forms of an existing drug.
Reference standard A chemical or generic product has to be
compared with some standard dosage form to verify its in-vivo
performance·. In general, the Food and Drug Administration
(FDA) accepts any innovator's drug product as a reference
standard.
Sampling: The biological sample to be used in the study has to
be decided before the commencement of a bioavailability
study. Two techniques :
Invasive : during blood collection. For morphologic study
like toxicity study, cumulation factor distinction.
Noninvasive : urine sample collection for measuring drug
half life.
The advantages of urinary excretion studies are:
it involves non-invasive method of sampling
the concentration of the drug in the urine is often greater
than that in blood/serum allowing easy estimation of the
drug
the amount of the drug excreted in urine is obtained
directly.
urinary excretion method has several disadvantages as
well.
urinary excretion studies are not useful in estimating the
absorption rate of a rapidly absorbing drug.
In some cases, the metabolites of the drug are also
concentrated in the sample that interferes with the
estimation of the unchanged drug in the urine sample.
Data collection problem as volunteers have to keep
bladder full for constant urination
Volunteer: age, sex ,physical state same. Bp, respiration, pulse,
every parameters should be checked.

Analytical instruments :
Clearance The rate of elimination of a drug from the body is
directly proportional to the plasma concentration.
Systemic clearance describes the efficiency with which drugs
are permanently eliminated from the body. Both drug input
rate (dosage rate) and systemic clearance determine the
average steady state plasma concentrations of a drug.
Metabolic clearance(MCR) is defined as the volume of blood
irreversibly cleared of a substance in time (usually about
1500L/day in case of aldosterone).