biopharmaceutics

1. Mechanism of drug absorption

2. Mechanism of drug absorption
The main mechanisms by which absorption
occurs include:
(a) Transcellular or intracellular transport
(b) Paracellular or intercellular transport
(c) Vesicular transport or endocytosis

3. • Transcellular/Intracellular Transport is
defined as the passage of drugs across the GI
epithelium. It is the most common pathway for
drug transport.
• Paracellular/Intercellular Transport – is
defined as the transport of drugs through the junctions
between the GI epithelial cells. This pathway is of
minor importance in drug absorption.

4. • Vesicular or Corpuscular Transport
(Endocytosis) – Like active transport, these are
also energy dependent processes but involve transport
of substances within vesicles into a cell. Since the
mechanism involves transport across the cell
membrane, the process can also be classified as
transcellular.

6. 1.Passive transport process
These processes don’t required energy other than that of
molecular motion to pass through the lipid bilayer .
Passive transport process can be further classified into :
• Passive diffusion
• Pore transport
• Ion pair transport

7. • PASSIVE DIFFUSION
• Drug molecule diffuse from a region of higher concentration to
region of lower concentration until equilibrium is attained.
• Major process for absorption of more than 90% of drugs
• Non ionic diffusion
• Driving force – concentration or electrochemical gradient
• Difference in the drug concentration on either side of the
membrane
• Drug movement is a result of kinetic energy of molecules
• Fick’s First law of diffusion

8. • Where, dQ/dt = rate of drug diffusion
(amount/time)
• D = diffusion coefficient of the drug
• A= surface area of the absorbing membrane for
drug diffusion
• Km/w = partition coefficient of drug between the
lipoidal membrane & the aqueous GI fluids
• (CGIT – C) = difference in the concentration of
drug in the GI fluids & the plasma (Concentration
Gradient)
• h = thickness of the membrane

10. • Characteristics of Passive diffusion:
• Energy independent
• Greater the area & lesser the thickness of the
membrane, faster the diffusion
• The process rapid over for short distances
• Concentration equal on both the sides of the
membrane - Equilibrium is attained
The passively absorbed drug enters blood, rapidly swept
away & distributed into a larger volume of body fluids.
Hence, the concentration of drug at absorption site
CGIT is maintained greater than the concentration in the
plasma. Such a condition is called as sink condition for
drug absorption.

11. • PORE TRANSPORT
• It is also called as convective transport, bulk flow or
filtration.
• Mechanism – through the protein channel present in the
cell membrane.
• Drug permeation through pore transport – renal excretion,
removal of drug from CSF & entry of drug into the liver
• The driving force – hydrostatic or osmotic pressure
differences across the membrane. Thus, bulk flow of
water along with the small solid molecules through
aqueous channels. Water flux that promotes such a
transport is called as solvent drag
• The process is important in the absorption of low
molecular weight (<100D), low molecular size (smaller
than the diameter of the pore) & generally water soluble
drugs through narrow, aqueous filled channels or pores
e.g. urea, water & sugars.
• Chain like or linear compounds (upto 400D)- filtration

12. • ION-PAIR TRANSPORT
• Responsible for absorption of compounds which
ionizes at all pH values. e.g. quaternary ammonium,
sulphonic acids
• Ionized moieties forms neutral complexes with
endogenous ions which have both the required
lipophilicity & aqueous solubility for passive
diffusion.
• E.g. Propranolol, a basic drug that forms an ion pair
with oleic acid & is absorbed by this mechanism

14. 2.CARRIER MEDIATED
TRANSPORT
• Involves a carrier which reversibly binds to the
solute molecules and forms a solute-carrier
complex.
• This molecule transverse across the membrane to the
other side and dissociates, yielding the solute
molecule.
• The carrier then returns to the original site to accept a
new molecule.

15. • There are two type of carrier mediated transport
system
• a) Facilitated diffusion
• b) Active transport

16. • Facilitated diffusion
• Facilitated diffusion is a form of carrier transport
that does not require the expenditure of cellular
energy.
• Carriers are numerous in number & are found
dissolved in cell membrane.
• The driving force is concentration gradient,
particles move from a region of high concentration
to low conc.
• The transport is aided by integral membrane
proteins.
• Facilitated diffusion mediates the absorption of
some simple sugars, steroids, amino acids and
pyrimidines from the small intestine and their
subsequent transfer across cell membranes.

18. • ACTIVE TRANSPORT
• It is characterized by the transport of drug against
concentration gradient with using energy. Requires
energy, which is provided by hydrolysis of ATP for
transportation
• More commonly, metabolic energy is provided by
the active transport of Na+, or is dependent on the
electrochemical gradient produced by the sodium
pump, Na+/K+ ATPase (secondary active transport).
• a) Primary Active Transport
• b) Secondary Active Transport

20. • a) Primary Active Transport
• Direct ATP requirement
• The process transfers only one ion or molecule & only in one
direction. Hence, called as UNIPORT E.g. absorption of
glucose
• Carrier proteins involved in primary active transport are of two
types :
• Ion transporters
• ABC (ATP binding Cassette) transporters
• b) Secondary Active Transport
• No direct requirement of ATP
• The energy required in transporting an ion aids transport of
another ion or molecule (co-transport or coupled transport)
either in the same direction or opposite direction.
• The process are further subdivided into two types :
• Symport (co-transport)
• Antiport (counter transport)

22. 3)Vesicular transport or endocytosis
• ENDOCYTOSIS
• It is a process in which cell absorbs molecules by
engulfing them.
• Also termed as vesicular transport
• Minor transport mechanism involving engulfing
extracellular materials within segment of cell
membrane to form a saccule or vesicle then
pinched of intracellularly.
• It occurs by 3 mechanisms:
• Phagocytosis
• Pinocytosis
• Transcytosis

24. • Phagocytosis (cell eating) : adsorptive uptake of solid
particulates
• PINOCYTOSIS (cell drinking):
• It is a form of endocytosis in which small particles are brought to
the cell, forming an invagination.
• These small particles are suspended in small vesicles.
• It requires energy in the form of ATP.
• It works as phagocytosis, the only difference being, it is non
specific in the substances it transports.
• This process is important in the absorption of oil soluble vitamins
& in the uptake of nutrients
• TRANSCYTOSIS
• It is the process through which various macromolecules are
transferred across the cell membrane.
• They are captured in vesicles, on one side of the cell and the
endocytic vesicle is transferred from
• one extracellular compartment to another.
• Generally used for the transfer of IgA and insulin

25. Factors affecting Absorption of
Drugs

26. • Factors Related to Drugs:
• 1. Lipid water solubility
• Lipid water solubility coefficient is the ratio of
dissolution of drug in lipid as compared to water.
Greater the lipid water solubility coefficient, more is the
lipid solubility of the drug and greater is the absorption.
Less the coefficient, less is the lipid solubility and less is
the absorption.
• Water film exists on the membranes so part of
the drugs must be water soluble to cross this water film
• Drugs with benzene ring, hydrocarbon chain, steroid
nucleus and halogen groups in their structures are lipid
soluble.

27. • Drug pKa & lipophilicity & GI pH --- pH
partition hypothesis:
• pH – partition theory states that for drug compounds
of molecular weight more than 100, which are
primarily transported across the biomembrane by
passive diffusion, the process of absorption is
governed by
• pKa of drug
• The lipid solubility of the unionized drug
• pH at the absorption site.

28. • pKa of drug: Amount of drug that exist in unionized
form and in ionized form is a function of pKa of drug
& pH of the fluid at the absorption site and it can be
determined by Henderson-hesselbach equation:

29. • 2. Molecular size
• Smaller the molecular size of the drug, rapid is the absorption.
There exist different processes involved in absorption for
different molecular sizes. Those with a large molecular size
undergo endocytosis or facilitated diffusion, while those with
smaller molecular sizes utilize aqueous diffusion or lipid
channels.
• 3. Particle size
• Particle may be composed either of a single molecule or more
than hundred molecules. Larger is the particle size, slower will
be the diffusion and absorption and vice versa.

30. • 4. Degree of Ionization
• Different drugs are either acidic or basic and are present in
ionized or unionized form, which is given by their pKa values.
In the body, the ratio of the ionized and unionized forms depend
on the pH of the medium. Acidic drugs are unionized in the
acidic medium and basic drugs are unionized in the basic
medium. Acidic drugs are better absorbed from the acidic
compartment.
• 5. Physical Forms
• Drugs may exist as solids, liquids or gases. Gases are
rapidly absorbed than the liquids, while the liquids are
rapidly absorbed than the solids. Thus the drugs in syrup or
suspension form are rapidly absorbed than the tablets or
capsules. Volatile gases used in general anesthesia are
quickly absorbed through the pulmonary route.

31. • 6. Chemical Nature
• Chemical nature is responsible for the selection of
the route of administration of drug. Drugs that cannot
be absorbed through the intestines are given by
the parenteral route. Examples include heparin which is
large molecular weight, and cannot be given orally.
Simililarly, benzyl penicillin is degraded in the GIT, so
is given parenterally.
• Salt forms of drugs are better absorbed than the organic
compounds when given orally. The organic compounds
are given by routes other than the oral or enteral route.
• Drugs in inorganic form are better absorbed than
organic forms e.g. iron in Fe+2 is better absorbed than
Fe+3.

32. • 7. Dosage Forms
• Dosage forms affect the rate and extent of absorption. A drug can be given in
the form of tablets, capsules or transdermal packets. Injections may be aqueous
or oily. This changes the rate of absorption. Examples include nitroglycerin
which when given by sublingual route, disintegrates rapidly but stays for a
shorter duration. When it is given orally, it disintegrates slowly and stays for
longer duration. When given by transdermal route, the drug can cover an even
longer duration.
• a. Disintegration:
• Disintegration is the breaking up of the dosage form into smaller particles.
When rapid is the disintegration, rapid will be the absorption.
• b. Dissolution:
• After disintegration, the drug dissolves in the gastric juices, which is called
dissolution. It is only then that the drug can be absorbed.
• When these two processes occur rapidly, the rate of absorption increases.

33. • 8. Formulation
• When the drugs are formed, apart from the active form
some inert substances are included. These are the
diluents, excipients and the binders. Normally they are
inert, but if they interact, they can change
the bioavailability. Examples include Na+ which can
interact to decrease the absorption.
• 9. Concentration
• According to Fick’s law, higher the concentration more
flux occurs across the membrane. The rate is less affected
than the extent of absorption.

34. • Factors Related to Body
• 1. Area of Absorptive Surface
• Area of absorptive surface affects oral as well as
other routes. Most of the drugs are given orally
because of the large area of absorptive surface, so that
greater absorption occurs. Intestinal resection
decreases the surface area leading to a
decreased absorption. Similarly, when the topically
acting drugs are applied on a large surface area, they
are better absorbed.

35. • 2. Vascularity
• More the vascularity, more is the rate and extent
of absorption and vice versa. In shock, blood supply to
the GIT is less so the oral route of drug administration is
affected. The blood flow to the peripheries is decreased,
so absorption in those areas is diminished as well.
Therefore, intravenous route is preferred in case of
shock.
• 3. pH
• Acidic pH favors acidic drug absorption while basic pH
is better for basic drugs.

36. • 4. Presence of other Substances
• Foods or drugs may interact with the drugs to alter their
rate of absorption. Especially for the drugs given orally,
food can increase or decrease the absorption.
• Antihyperlipidemic drugs like the statins are
better absorbed when taken with the food.
• Iron when given with milk has decreased absorption.
• Vitamin C enhances the absorption of iron.
• Milk decreases the absorption of tetracyclines.
• Calcium salts when given with iron salts or tetracyclines
interfere with their absorption

37. • 5. GI Mobility
• GI mobility must be optimal for absorption of oral drugs.
It should be neither increased nor decreased which may
affect the rate or extent of absorption.
• Different diseases or drugs may alter the mobility.
Diarrhea causes rapid peristalsis, decreasing contact time
and thus the extent of absorption is affected more.
Constipation affects disintegration and dissolution so
decreases motility.
• Gastric emptying
• Apart from dissolution of a drug and its permeation
through the biomembrane, the passage from stomach to
the small intestine, called as gastric emptying, can also
be a rate-limiting step in drug absorption because the
major site of drug absorption is intestine. Thus, generally
speaking, rapid gastric emptying increases bioavailability
of a drug.

38. • 6. Functional Integrity of Absorptive Surface
• Flattening and edema of mucosa decreaes absorption.
Dysfunctional breach in the skin affects
the absorption of topical drugs.
• 7. Diseases
• Diarrhea
• Decreases absorption because of decreased contact time.

39. • 8. Presystemic or First pass metabolism
• The loss of drug as it passes through GIT
membrane, liver for the first time during the
absorption process.
• The main reason for the decrease in bioavailability
of a drug is decreased absorbtion or 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.

40. • Luminal enzymes: These are enzymes present in
gut fluids and include enzymes from intestinal and
pancreatic secretions. E.g. hydrolases
• Gut wall enzymes: Also called mucosal enzymes
they are present in gut and intestine, colon. E.g. alcohol
dehydrogenase
• Bacterial enzymes: GI microfloras scantily present
in stomach and small intestine and are rich in colon.
e.g. sulphasalazine sulphapyridine + 5 ASA
• Hepatic enzyme: several drug undergo firstpass
hepatic metabolism, highly extracted ones being
isoprenaline, nitroglycerin, morphine etc.

41. 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

42. • 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,
• Rapid absorption and higher blood levels
• No first pass metabolism
• No degradation of drugs such as that encountered
in the GIT
• Presence of saliva facilitates both drug dissolution
and permeation.

43. • Rectal Administration
• An important route for children and old patients.
• The drug may be administered as solution or
suppositories.
• By passes the presystemic hepatic metabolism.
• Drug administered by this route includes
• Aspirin, paracetamol, few barbiturates.
• Alternative route for administration of unpleasant
drugs
• Avoids nausea, vomiting
• Can be used in case of unconscious patients
• Bypasses presystemic hepatic metabolism from
lower half of rectum.

44. • 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.
• Transdermal route-
• This route of administration achieves systemic effects by
application of drugs to the skin, usually via a
transdermal medicated adhesive patch.
• The rate of absorption can vary markedly, depending on
the physical characteristics of the drug (lipid soluble)
and skin at the site of application.

45. • INJECTIONS
• Intravenous (IV) Injection.
• Drug is directly goes into blood stream
• Intramuscular (IM) Injection.
• Absorption of drugs from I.M. sites is relatively
rapid but much slower than I.V. injection.
• Subcutaneous (SC) Injection.
• Absorption is slower than I.M. site due to poor
perfusion
• Intraperitoneal (IP) Injection.
• I.P.route is rarely employed in human beings but
most widely used in laboratory animals

46. • 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

47. • Intranasal administration
• Drug absorption by this route is as rapid as parenteral
administered because of its high permeability and rich
vasculature.
• Popular for administration of peptides and protein
drugs.
• Route treat local symptoms like nasal congestion,
rhinitis.
• Absorption depends upon drug lipophilicity and
molecular weight.
• Rapid absorption by diffusion is observed up to 400 -
1000 dalt.

48. • 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.
• The addition of viscosity increasing agents in the
ophthalmic solution will increases occular
bioavailability.
• Ex: pilocarpine, timmolol, atropine.

49. • 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.