absorption of drugs

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ABSORPTION PROCESS AND FACTORS EFFECTING ORAL
DRUG ABSORPTION
BY VENKATA NAVEEN KASAGANA SWATHI SREE
KARUMURI M-PHARM -PHARMACEUTICS S.B. COLLEGE OF
PHARMACY SIVAKASI TAMIL NADU INDIA E-MAILnaveen.k
asagana_at_gmail.com
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Absorption Absorption may be defined as the
process by which a compound penetrates one or
more biological membranes to gain entry into the
body. An orally administered drug that undergoes
extensive firstpass hepatic clearance may give
rise to poor oral bioavailability despite being
efficiently absorbed from the gastrointestinal
(GI) tract.
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• Mechanism of drug absorption
• Following the administration of a drug in a
  dosage form, drug molecules must somehow gain
  access to the bloodstream, where the distribution
  process will take it to the site of action.
• For absorption to occur, therefore, the drug
  molecule must first pass through a membrane.
• Membrane physiology the gastrointestinal barrier
• It is made up of lipids, proteins, lipoproteins
  and polysaccharide material
• It is semipermeable in nature or selectively
  permeable (i.e. allowing rapid passage of some
  chemicals while restricting others).

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INTRODUCTION

• DRUG ABSORPTION Movement of unchanged drug from
  site of administration to systemic circulation.

Fig- Plots showing significance of rate extent
of absorption in drug therapy
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GASTROINTESTINAL ABSORPTION OF DRUGS

• Oral route is most common ROA for systemically
  acting drugs so more emphasis is given to GI
  drug absorption.
• It includes all aspects of variability observed
  in drug absorption.
• CELL MEMBRANE - Cell membrane structure
  Physiology

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MECHANISM OF DRUG ABSORPTION

• Passive diffusion
• Pore transport
• Facilitated diffusion
• Active transport
• Ionic or Electrochemical diffusion
• Ion-Pair transport
• Endocytosis

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Figures showing different types of
transport Mechanisms.
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• Passive diffusion
• The membrane plays a passive role in drug
  absorption during passive diffusion most drugs
  pass through membrane by this mechanism.
• The rate of drug transfer is determined by the
  physicochemical properties of the drug and the
  drug concentration gradient across the membrane.
• The driving force for the movement of drug
  molecules from the gastrointestinal fluid to the
  blood is the drug concentration gradient (i.e.
  the difference between the concentration of drug
  in the gastrointestinal fluid and that in the
  bloodstream).
• The passage of drug molecules through the
  membrane being a continuous process, there will
  always be an appreciable concentration gradient
  between the gastrointestinal tract and the
  bloodstream (because of volume differences),which,
  in turn, will yield a continuous drug transfer
  and maintain a so-called sink condition.
• Passive diffusion or transfer follows first-order
  kinetics (i.e. the rate of transfer is directly
  proportional to the concentration of drug at
  absorption and/or measurement sites).

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• Active transport
• Chemical carriers in the membrane combine with
  drug molecules and carry them through the
  membrane to be discharged on the other side.
• This process is called active transport because
  the membrane plays an active role.
• Important features are that chemical energy is
  needed and that molecules can be transferred from
  a region of low concentration to one of higher
  concentration (i.e. against a concentration
  gradient.)
• The striking difference between active and
  passive transport, however, is that active
  transport is a saturable process and, therefore,
  obeys laws of saturation or enzyme kinetics.
• The rate of absorption reaches a saturation
  point, at which time an increase in drug
  concentration (larger doses) does not result in a
  directly proportional increase in the rate of
  absorption.
• This is because of a limited number of carriers
  in the membrane.

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• where Vmax is the theoretical maximum rate of the
  process
• Km is the MichaelisMenten constant (i.e. the
  concentration of drug at the absorption site when
  the absorption rate is half of Vmax)
• 3. Ca is the concentration of drug at the
  absorption site (e.g. in the gastrointestinal
  tract) at a given time.
• At low solute concentration (i.e. at low
  doses)KmCa

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• pH--partition theory of drug absorption
• The dissociation constant, expressed as pKa, the
  lipid solubility of a drug, as well as the pH at
  the absorption site often dictate the magnitude
  of the absorption of a drug following its
  availability as a solution.
• The interrelationship among these parameters (pH,
  pKa and lipid solubility) is known as the
  pHpartition theory of drug absorption.
• This theory is based on the following
  assumptions
• 1. The drug is absorbed by passive transfer
• 2. The drug is preferentially absorbed in
  unionized form
• 3. The drug is sufficiently lipid soluble.
• The fraction of drug available in unionized form
  is a function of both the dissociation constant
  of the drug and the pH of the solution at the
  site of administration.
• The dissociation constant, for both acids and
  bases, is often expressed as log Ka, referred to
  as pKa.

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For weak acids Ionization of weak acids is
described by an adaptation of a classical
HendersonHasselbalch equation.

• This equation clearly indicates that the ratio of
  ionized/unionized species, a/(1a), is solely
  dependent upon pH and the pKa.
• For weak acids
• when pH¼pKa, a¼0.5, or 50 of the drug is in
  ionized form
• when pH is 1 unit greater than pKa, a¼0.909,or
  90 of the drug, is in ionized form
• when pH is 2 units greater than pKa, a¼0.99, or
  99 of the drug, is in ionized form
• when pH is 1 unit below pKa, 1a¼0.9, or 90 of
  the drug, is in unionized form
• when pH is 2 unit below pKa, 1a¼0.99, or 99 of
  the drug, is in unionized form.

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For weak bases For weak bases, the
HendersonHasselbalch equation is

• when pH¼pKa, a¼0.5, or 50 of the drug is in
  the ionized form
• when pH is 1 unit below pKa, a¼0.909, or 90
  of the drug, is in the ionized form
• when pH is 2 units below pKa, a¼0.99, or 99
  of the drug, is in the ionized form
• when pH is 1 unit above the pKa of the
  drug,1a¼0.909, or 90 of the drug, is
• present in unionized form
• when pH is 2 units above pKa, 1a¼0.99, or 99
  of the drug, is present in unionized
• form.
• As the pH of the solution increases, the degree
  of ionization (percentage ionized) decreases.
• Therefore, weak basic drugs are preferentially
  absorbed at higher pH.
• Examples
• Aspirin, a weak acid with pKa of 3.473.50,has a
  greater fraction ionized in a more alkaline
  (higher pH) environment
• Erythromycin, a weak base with pKa of 8.7, has a
  greater fraction ionized in a more acidic (lower
  pH) environment.

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• Physicochemical properties of drug substances
• Drug solubility Dissolution rate
• Particle size Effective surface area
• Polymorphism Amorphism
• Pseudo polymorphism ( hydrates/ solvates)
• Salt form of the drug
• Lipophilicity of the drug
• pKa of the drug p H
• Drug stability

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• Dissolution rate
• In order for absorption to occur, a drug or a
  therapeutic agent must be present in solution
  form.
• This means that drugs administered orally in
  solid dosage forms (tablet, capsule, etc.) or as
  a suspension (in which disintegration but not
  dissolution has occurred) must dissolve in the
  gastrointestinal (GI) fluids before absorption
  can occur

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• There are two possible scenarios for drug
  dissolution
• Absorption from solution takes place following
  the rapid dissolution of solid particles. In this
  case, the absorption rate is controlled by the
  rate of diffusion of drug molecules in GI fluids
  and/or through the membrane barrier.
• 2. Absorption from solution takes place following
  slow dissolution of solid
• particles. In this process, the appearance of
  drug in the blood (absorption) is
• controlled by the availability of drug from
  solid particles into the GI fluid
• (i.e. dissolution is the rate-limiting step).
  
• Hence, the rate of absorption and bioavailability
  are dependent upon how fast the drug dissolves in
  the GI fluid.
• Generally, for hydrophobic drugs, the rate of
  absorption and bioavailability may be improved by
  increasing the rate of dissolution.

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Noyes--Whitney equation and drug dissolution The
NoyesWhitney equation was developed from careful
observation of the dissolution behavior of
solids in a solvent system

• The specific dissolution rate constant (K1) is a
  constant for a specific set of conditions,
  although it is dependent on temperature,
  viscosity,agitation or stirring (which alters the
  thickness of diffusion layer) and volume of the
  solvent.
• The NoyesWhitney equation tells us that the
  dissolution rate (dC/dt) of a drug in the GI
  tract depends on
• 1. diffusion coefficient (D) of a drug
• 2. surface area (S) of the undissolved solid drug
• 3. saturation, or equilibrium, solubility (Cs) of
  the drug in the GI fluid
• 4. thickness of the diffusion layer (h).
• dCdt ¼ KDShCs

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• Surface area and particle size
• Of all possible manipulations of the
  physicochemical properties of drugs to yield
  better dissolution, the reduction of the particle
  size of the drug has been the most thoroughly
  investigated.
• A drug dissolves more rapidly when its surface
  area is increased.
• This increase in surface area is accomplished by
  reducing the particle size of the drug.
• This is the reason why many poorly soluble and
  slowly dissolving drugs are marketed in
  micronized or microcrystalline form (i.e.
  Particle size of 210 mm).

• Drugs where bioavailability has been increased as
  a result of particle size reduction
• Aspirin
• Bishydroxycoumarin
• Chloramphenicol
• Digoxin
• Fluocinolone acetonide
• Griseofulvin

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Solubility of a drug in the diffusion layer If
the solubility of a drug can be appreciably
increased in the diffusion layer, the drug
molecules can rapidly escape from the main
particle and travel to the absorption site.
This principle is used to increase the
solubility of weak acids in the stomach. The
solubility of weak acids increases with an
increase in pH because the acid is transformed
into an ionized form, which is soluble in aqueous
GI content. The pH of a solution in the
diffusion layer can be increased by using a
highly water-soluble salt of a weak acid
mixing or combining a basic substance into a
formulation (e.g. NaHCO3 sodium
bicarbonate,calcium carbonate, magnesium
oxide,and magnesium carbonate MgCO3)
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Crystalline forms Many drugs exist in more than
one crystalline form, a property known as
polymorphism. Drug molecules exhibit different
spacelattice arrangement in crystal form in each
polymorph. Though chemically the same, polymorphs
differ substantially with regards to
physicochemical properties.These properties
include solubility, dissolution rate, density and
melting point, among others.Solubility and
dissolution rate, in turn, will likely influence
the rate of Examples are 1.sulfameter This
sulfanilamide is reported to have six polymorphs.
State of hydration The state of hydration of a
drug molecule can affect some of the
physicochemical properties of a drug. One such
property that is significantly influenced by the
state of hydration is the aqueous solubility of
the drug. Often the anhydrous form of an organic
compound is more soluble than the hydrate (with
some exceptions). Complexation Formation of a
complex of drugs in the GI fluid may alter the
rate and, in some cases, the extent of
absorption. The complexing agent may be a
substance normal to the GI tract, a dietary
component or a component (excipient) of a dosage
form.
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Complexing with a substance in the
gastrointestinal tract Intestinal mucus, which
contains the polysaccharide mucin, can avidly
bind streptomycin and dihydrostreptomycin. This
binding may contribute to the poor absorption of
these antibiotics. Bile salts in the small
intestine interact with certain drugs, including
neomycin and kanamycin, to form insoluble and
non-absorbable complexes.
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Absorption of drug from Non-per oral route

• Buccal/Sublingual Administration
• Rectal Administration
• Topical Administration
• Inhalation Administration
• Intramuscular Administration
• Subcutaneous Administration
• Intranasal Administration
• Intraocular Administration
• Vaginal Administration

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Buccal/Sublingual Administration

• In buccal route the medicament is placed between
  the cheek and the gum.
• In sublingual the drug is placed under the
  tongue.
• Barrier to drug absorption from these route is
  epithelium of oral mucosa.
• Absorption of drug is by passive diffusion.
• Eg lozenges
• nitrates and nitrites,

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Rectal Administration

• An important route for children and old patients.
• The drug may be administered as solution or
  suppositories.
• Irritating suppositories bases such as PEG
  promotes defecation and drug loss, and presence
  of fecal matter retards drug absorption.
• By passes the presystemic hepatic metabolism.
• Drug administered by this route includes
• ExAspirin, paracetamol, few barbiturates.

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Topical Administration

• Skin is the largest organ in the body weighing
  around 2kg and 2mtsq in area and receives about
  1/3rd of total blood circulating through the
  body.
• Topical mode of administration is called as
  percutaneous or transdermal delivery.
• The drug act either locally or systemically.
• Drug that administered precutaneously include
  lidocaine, testosterone , estradiol, etc.

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Inhalations Administration

• All drugs intended for systemic effect can be
  administered by inhalation since the larger
  surface area of alveoli, higher permeability to
  the alveolar epithelium rapid absorption just
  exchange of gases in blood.
• Route has been limited for drugs such as
  bronchodilators, anti-inflammatory steroids and
  antiallergics.
• Drug do not under go first pass metabolism.
• lipid soluble drugs absorption rapid by passive
  diffusion and polar drug by pore transport.
• Generally administered by inhalation either as
  gases or aerosols

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Intra muscular injection

• degree of absorption will be Armsgt Thighgt
  Buttocks.
• These are given to the patients those who are
  unable to take oral medication.
• These route is used for the drugs that are poorly
  absorbed from the GIT.
• Lipophilic drugs absorbed rapidly by passive
  diffusion whereas hydrophilic drugs are slowly
  absorbed through capillary pores
• Ex-digoxin

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Subcutaneous injection

• Application of heat increase the blood flow.
• Local co administration of vasodilators.
• Absorption of the drug can be slowed by
  co-injection of a vasoconstrictor.
• Ex epinephrine
• Insulin, local anesthesia.

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Intraocular Administration

• Mainly for the treatment of local effects such as
  mydriasis, meiosis, anesthesia and glaucoma.
• The barrier in the occular membrane is called
  cornea which contains both hydrophilic and
  lipophilic characters.
• Thus for optimum intra occular permeation drug
  should posses biphasic solubility.
• pH of formulation influences lacrimal output.
• The addition of viscosity increasing agents in
  the ophthalmic solution will increases occular
  bio availability.
• Ex pilocarpine, timmolol, atropine.

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Vaginal Administration

• Available in various forms tablets, creams,
  ointments, douches and suppositories.
• Used for systemic delivery of contraceptive and
  other steroids.
• By passes first pass metabolism.
• Factors effecting drug absorption are
• -pH of the lumen fluid
  4-5.
• -vaginal secretions.
• -microbes at vaginal
  lumen.
• Bio availability of vaginal product was about 20
  more compared with oral.
• Ex steroidal drugs and contraceptives.

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Intra Nasal application

• Used for the systemic administration of drugs.
• Mainly contain decongestants, anti histamines,
  corticosteroids.
• Nasal mucosa are more permeable than gastric
  mucosa.
• Drugs directly traveled through blood stream no
  first pass metabolism.
• Peptides are not actively absorbed from nasal
  mucosa but can be promoted by surface active
  agents.
• Ex desmopressin acetate

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Physiological factors

• 1.Age
  
  2.Gastric Empting
  3.Intestinal Transit
  
  4.GI pH
  
  5.Blood Flow to GIT
  6.Diseased State
  
  7.GI Content
  8.First pass
  effect

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1. Age

• In infants GI pH is high and intestinal surface
  and blood flow to GIT is low as compared to
  adults results in poor drug absorption.
  
  
• In elderly people, alteration in drug absorption
  becuase of alteration in gastric emptying, and
  incidents of achlorhydria and bacterial over
  growth in small intestine.

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2. Gastric emptying

• Defined, as passage of contents of stomach into
  the intestine.
  
• Rapid gastric emptying is advisable where
• Rapid onset action is required, eg sedatives.
• Dissolution of drug occurs in intestine.
  eg Enteric coated tablets.
• Drug is unstable in gastric fluids.
• Drug is best absorbed from distal part of small
  intestine, eg vitamin B 12 .
  

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Kinetics of GI emptying

• GI emptying is first-order kinetics many
  parameters are used to quantify a gastric
  emptying
• 
  1.Gastric
  emptying rate Is the speed at which the stomach
  contents are emptied into the intestine.
• 
  
  2.Gastric emptying time Time required for the GI
  content to empty into small intestine.
• 
  3.G.E.t1/2
  Is time taken for half the stomach contents to
  empty.

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Factors affecting GI emptying

• 1.Volume of meals
  
  2.Composition of meal
  3.Physical state of
  meal
  4.GI ph
  5.Body posture
  
  6.Emotional state
  
  7.Exercise
  8.Drugs

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• 1.Volume of meal Larger the bulk of the meal,
  longer the gastric time and however an initial
  rapid rate of emptying is observed with large
  meal volume and initial lag phase in emptying of
  small volume meals.
• 2.Composition of meal The rate of gastric
  emptying for various food materials in the
  following order carbohydratesgtproteinsgtfats.
• 3.Physical state Liquid meal takes less
  time as compared to solid meals.
• 
  
  4.GI ph Gastric emptying is
  retarded at low stomach pH and promoted at
  alkaline pH.
  

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• 5.Exercise Vigorous physical training retards
  gastric empting.
• 6.Body posture Gastric emptying is favored
  while standing and by lying on right side.
• 7. Emotional state Stress and anxiety
  promotes GI motility, where as depression retards
  it.
• 8.Drugs That retards gastric emptying are
  antacids, anti cholinergic, narcotic analgesics
  and tri cyclic antidepressants.

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3. Intestinal transit

• Defined as, the residence time of drug in small
  intestine.
  
• Delayed intestinal transit is desirable for
  
• 1.Sustained release dosage forms,
  
• 2.Drug that only release in intestine ie ,enteric
  coated formulations,
  
• 3.Drugs absorbed from specific sites in
  intestine, eg several B vitamins

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4. GI pH

• GI pH influence in several ways
  
  1.Disintegration
  Disintegrating of some dosage forms is pH
  sensitive, enteric coated tabs dissolve only in
  alkaline pH.
  
  2.Dissolution A large no. of drugs either weak
  acids or weak bases, their solubility is greatly
  affected by GI pH.
  
  -weakly
  acidic drugs dissolve rapidly in alkaline pH.
  
  -basic drugs soluble in acidic pH..
  
  3.Absorption Depending upon drug pKa whether
  its an acidic or basic drug the GI pH influences
  drug absorption.
• 4.stability of drug GI pH influence the
  stability of drug.
• Eg erythromicin

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5. Blood flow to git

• GIT is extensively supplied by blood capillary,
  about 28 of cardiac output is supplied to GIT
  portion, most drug reach the systemic
  circulation via blood only.
• Any factor which affects blood flow to GIT may
  also affect absorption.

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6. Disease state

• Several disease state may influence the rate
  and extent of drug absorption.
• Three major classes of disease may influence
  bioavailability of drug.
• GI diseases
• CVS disease
• HEPATIC disease

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GI diseases

• A. GI infections
  
• 1.Celiac disease (characterized by destruction
  of villi and microvilli) abnormalities associated
  with this disease are increase GI emptying rate
  and GI permeability, alter intestinal drug
  metabolism.
• 2.Crohns disease alter gut transit time and
  decreased gut surface area.
  
• B. GI surgery
• Gastrectomy may cause drug dumping in intestine,
  osmotic diarrhoea and reduce intestinal transit
  time.
  

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CVS diseases

• In CVS diseases blood flow to GIT decrease,
  causes decreased drug absorption.

Hepatic diseases
Disorders like hepatic cirrhosis influences
bioavailability of drugs which under goes first
pass metabolism.
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7. Gastro intestinal contents

• 1.Food- drug interaction In general
  presence of food either delay, reduce, increase
  or may not affect absorption.
• Aspirin Delayed
• Penicillin's Decreased
• Griseofulvin Increased
• Methyldopa Unaffected
• 2.Interaction of drug with normal GI contents
  GIT contains no. of normal constituents such as
  mucin, bile salts and enzymes, which influence
  the drug absorption. Eg Inhibitory action of
  bile on GI motility.
  
  
  

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• 3.Drug-Drug interaction in the GIT
• Physico chemical drug- drug interaction
  
• Adsorption Eg anti diarrhial preparations
  contains adsorbents like kaolin, prevents a
  absorption of many drugs co-administered with
  them.
  
• Complexation Eg penicillin derivative with
  ca-gluconate.
  
  
• pH changes Basic drugs changes gastric pH
• Eg tetracycline with antacids
  

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8. First pass metabolism

• Four primary systems which affect pre systemic
  metabolism of a drugs.
  1. Luminal enzymes.
  
  2.Gut wall enzymes or mucosal enzymes.
  3. Bacterial enzymes.
  4.
  Hepatic enzymes.

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Pharmaceutical Factors

• Different dosage forms-
• Solutions Suspensions
• Tablets Capsules
• Coated tab Enteric coated tab
  
• Disintegration test
• Dissolution test
• Excipients and adjuvant
• Product age and storage conditions.

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FACTORS INFLUENCING DRUG ABSORPTION

• By proper biopharmacetic design, the rate
  extent of drug absorption (BA) / systemic
  delivery of drug to the body can be varied from
  rapid complete absorption to slow sustained
  absorption depending upon desired therapeutic
  objective.
• Sequence of events that occur following
  administration of solid dosage form until its
  absorption in systemic circulation.
• Rate at which drug reaches systemic circulation
  is determined by slowest of the various steps
  involved in sequence. Such a step is called as
  Rate- determining/ Rate- limiting step (RDS)

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Dosage forms

• Order of bioavailability of drugs.
• Solutionsgtsuspensionsgtcapsulesgttabletsgtcoated
  tablets
• SOLUTIONS
• Drugs absorbed more rapidly in this form.
• When this formulation is taken after meal gastric
  emptying is the rate limiting step.
• Factors influencing are
• Nature of the solvent, viscosity, surfactant,
  solubilisers, stabilizers.
• Drugs which are poorly soluble can be converted
  to water soluble by the addition of co solvents
  such as alcohol, propylene glycol etc

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Suspensions

• Dissolution is the rate limiting step for the
  absorption of the drug from suspension.
• Factors to considered for drug bioavailability
  are,
• particle size ,
• wetting agents ,
• viscosity of the medium,
• suspending agents.

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• For hard gelatin capsules the shell should
  disrupt quickly and expose the contents to the GI
  fluids.
• Factors influencing are particle size, density,
  crystal form of the drug, selection of diluents.
• soft elastic capsule dissolve faster than hard
  gelatin capsule tablets. Which shows better
  bioavailability from oily solutions, emulsions,
  or suspensions.
• The problem with SGC is high water content of
  shell, moisture migrate in to the shell causes
  crystallization of the drug results in altered
  dissolution characteristics .

Capsules
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Tablets

• This is the most widely used dosage form.
• Problem with this arises from reduction in the
  effective surface area due to granulation
  subsequent compression in to dosage form.
• Tab disintegration and granule deaggreation are
  the imp steps in absorption process.
• Compression force also may be an important
  factor.
• Disintegration is the rate limiting step for
  this.

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Coated tablets

• Coat is generally used to mask unpleasant taste
  odor to protect the ingredients from
  decomposition during storage.
• This adds an additional barrier between GIT
  drug. It should get dissolve before tablet
  disintegration dissolution.
• Sugar film coatings
• Sugar coating will take more time than film
  coating.
• Care should be taken while selecting the coating
  material
• Ex methyl cellulose which retards the dissolution

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Enteric coated tablets

• It is a special film coated design to restricts
  the gastric fluids to dissolve in small
  intestine.
• Protect the drug from the degradation in the
  stomach Ex erythromycin.
• Minimize the gastric distress caused by some
  drugs. Ex aspirin.
• These tablets must empty the stomach before the
  drug absorption can begin.
• The polymers with pKa values ranging from 4-7
  have been found to use.
• Thickness of coating will effects the
  bioavailability in these formulations.

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Pharmaceutical Excipients
Excipients are add to ensure the acceptability,
physiochemical stability, bioavailability and
functionability of the drug product. More the
number of excipients in a dosage form, the more
complex and greater the absorption and
bioavailability problems.
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Commonly used excipients Diluents
Binders Disintegrants Lubricants
Coatings Suspending agents Surfactants Buffers C
omplexing agents Colorants Sweeteners.
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Product Age and Storage Condition

• A number of changes, especially in the
  physiochemical properties of a drug in a dosage
  from, can result due to aging and alteration in
  storage conditions which can adversely affect
  bioavailability.
• Solution dosage form.
• Solid dosage form.

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DISINTEGRATION

• It is provided to determine the compliance with
  the limit on disintegration stated in the
  individual monograph.
• Formulation tested are
• un coated tab, plain coated, enteric
  coated, buccal, sub lingual, hard gelatin capsule
• For un coated tab and capsules the time is 30
  mins. where as for coated tab it is 2 hrs.
• Disintegration can be aided by incorporating
  disintegrants in suitable amount during
  formulation .

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DISSOLUTION

• The development of this test predicts the drug
  absorption.
• It shows close relation b/w drug absorption and
  dissolution rather than disintegration.
• By using USP apparatus
• type1- basket method
• type2- paddle method
• Basket method- the basket containing tab and
  capsules are immersed in the dissolution fluid
  and rotated .
• Paddle method-the dosage form is placed directly
  in the dissolution medium and paddle is rotated.
• Fluids may be water , HCL, buffer maintained at
  370c.
• The samples are removed at desired interval and
  assayed for drug content.

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METHODS OF DETERMINING ABSORPTION

• IN-SITU AND IN-VIVO
  
  
• METHODS

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• IN-SITU METHODS
• These absorption models permits the
  study of individual organ processes site
  specific absorption.
• The tissue is maintained intact with
  blood flow to the organ. Samples of drug solution
  from in-situ loop experiments can be obtained to
  measure the drug disappearance metabolite
  formation.

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DIFFERENT METHODS USED

• 1) Absorption from small Intestine
• A) Perfusion technique.
• B) Intestinal loop technique.
• 2) Absorption from stomach.
• 3) Perfusion Intestine-Liver
• preparation.

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• 1) ABSORPTION FROM SMALL INTESTINE
• Perfusion Technique
• Method-1
• In this method adult male rats are fasted for
  about 16-24 hours before the experiment.
• The animal is anaesthesised, a midline abdominal
  incision is made the small intestine is
  isolated cannulated at the duodenal ileal
  ends with polyethylene cannulas of internal
  diameter 2.5mm external diameter of 3.5mm.
• The stomach cecum are closed off by ligature
  the intestine is then replaced in the rats
  abdominal cavity.

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• The incision is closed the duodenal cannula is
  attached to an infusion pump.
• Initially the intestine is cleared off
  particulate matter using drug free buffer at a
  rate of 1.5 ml/min for 30 minutes.
• Next, buffer solution containing the drug is
  perfused at a rate of 1.5 ml/minute for 30
  minutes.
• Then, samples at 10 minutes interval are
  collected from the ileal cannula.

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• The samples are assayed for drug content the
  relative rate of absorption is calculated from
  the difference in the drug concentration entering
  leaving the small intestine.
• This method was used to demonstrate the validity
  of the pH partition hypothesis for the intestinal
  absorption of a variety of weakly acidic basic
  drugs.

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• Method-2
• Doluisio and coworkers have reported a
  simple reproducible method for studying
  intestinal absorption of drugs in rats.
• A rat that has been fasted overnight is
  anaesthetized ( intraperitoneally with urethane),
  a midline abdominal incision is made the
  intestinal segment (usually jejunal) to be
  perfused is identified.
• A-L shaped glass inlet cannula is secured into
  the segment the outlet cannula is placed
  approximately 15-50 cm from the inlet cannula.

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• These are secured with sutures the intestine
  is replaced in the abdominal cavity.

Rat perfusion technique
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• A 30 ml hypodermic syringe equipped with a three
  way stopcock containing perfusion solution at
  37C is attached to the duodenal cannula.
• Then the intestinal lumen is cleared off
  particulate matter by introducing the solution
  from the syringe.
• The syringe is then filled with drug solution
  10ml volume is introduced into the intestine.

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• An identical syringe is affixed to the ileal
  cannula.At appropriate time intervals,the
  solution in the intestine is pumped into either
  syringe a 0.1ml sample is removed assayed for
  drug content.
• Alternatively, the compound is perfused through
  the segment with an infusion pump at a constant
  rate for 120 minutes. Outflow samples are
  collected at predetermined time intervals both
  influent effluent are assayed for the
  compound.

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• B) Intestinal Loop Technique
• Adult male rat are fasted over night.
• Under anesthesia an abdominal midline incision
  is made the small intestine is exposed.
• A proximal ligature is loosely placed around the
  intestine about 6 from the pylorus a distal
  ligature is secured at a distance of
  approximately 4 distal to proximal ligature.

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• The drug solution is introduced into the lumen
  of loop by means of a syringe which is secured by
  the proximal ligature.
• After injection, needle is removed, the proximal
  ligature is tightened, the loop is replaced into
  the abdominal cavity the incision is closed.
• After a predetermined period of time, the animal
  is sacrificed, the intestinal loop is rapidly
  excised homogenized the amount of drug
  unabsorbed is determined.

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• 2) ABSORPTION FROM STOMACH
• Fasted adult male rats are anaesthetized,
  stomach is exposed the cardiac end is ligated.
• An incision is made in the pylorus in which a
  cannula is introduced ligated.
• The lumen is washed several times with saline
  subsequently with 0.1N HCl solution containing
  0.15M NaCl.
• The drug solution of known concentration is
  introduced into stomach.

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• After 1hr, the solution is removed from the
  gastric pouch assayed for drug content.
• The percentage of drug absorbed in 1hr may be
  calculated.
• The gastric pouch may also be
  homogenized analyzed for drug.
• In order to obtain number of samples as
  a function of time, the following modification is
  done.
• Drug solution is introduced into the gastric
  lumen via cardiac cannula.

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• A polyethylene tubing connected to a 2ml syringe
  equipped with a three way stopcock is attached to
  the duodenal L shaped glass cannula.
• At appropriate intervals the stomach contents
  are sampled by withdrawing about 0.5ml of
  solution into the syringe, removing 0.1ml of
  aliquot returning the reminder.

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3) PERFUSED INTESTINE-LIVER PREPARATIONS

• This technique use a direct approach to examine
  the contribution of each organ/tissue in the
  first pass metabolism can be used to study the
  sequential processing of drug metabolites by
  the intestine liver.

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• A schematic illustration of the once through
  vascularly perfused rat intestine-liver
  preparation is shown in below figure.

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• where, QHV Hepatic venous flow
• QPV Hepatic portal flow
• QHA Hepatic artery flow
• CPV Steady- state drug
• concentration in the
  portal vein
• CHV Steady- state drug
• concentration in the
  hepatic vein
• The superior mesentric artery the hepatic
  artery are cannulated for the inflow of
  oxygenated perfusate to the intestine liver
  respectively.

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• The bile duct can also be cannulated to obtain
  or to permit full collection of bile.
• The portal vein is cannulated for sampling of
  venous perfusate from the intestine.
• In addition, the outflow from the hepatic vein
  can be sampled.
• The model is flexible permits manipulation of
  the flow, intestinal site concentration
  perfusate.

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Some Applications of perfused intestine liver
studies.

• Application
• Measuring extraction ratios
• 2) Investigate intestinal metabolism

• Examples
• Determine the steady-state extraction ratio of
  enalpril in the intestine liver.
• The intestine is responsible for the formulation
  of most of 4-methylumbeliferone glucuronide.

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IN-VIVO METHODS

• IN-VIVO Methods can classified into-
• Direct method.
• Indirect method.
• 1)DIRECT METHOD
• In this method, the drug levels in blood or urine
  is determined as a function of time.
• A blank urine or blood sample is taken from the
  animal before experiment.
• The test dosage form is then administered

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• to the animal at appropriate intervals of
  time the blood or urine samples are collected
  assayed for drug content.
• From the data, we can determine the rate
  extent of drug absorption.
• 2) INDIRECT METHOD
• In this method, the pharmacologic response is
  taken as the index of drug absorption.
• Here, Assumption is made that the pharmacologic
  response of a drug is related to the amount of
  drug in the body, the response is determined
  after the administration of a test dosage form.
  

• LD50 appears to be dependent on the rate of
  absorption of the drug hence on the rate of
  dissolution.

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References

1. Peter.G.Welling et.Al pharmacokinetics 2nd
   edition marcel dekker inc new york32-33.
2. Dr.Shobha rani r.Hiremath textbook
   biopharmaceutics and pharmacokinetics prism
   books private limited banglore28-31
3. D.M.Brahmankar, sunil b. Jaswal biopharmaceutics
   and pharmakokinetics. Ist ed., Vallabh
   prakashan-delhi 1995. P.39-71.

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