Physiological factors such as the route of administration, gastrointestinal pH, motility and emptying time, presence of food, and disease states can impact drug absorption from the gastrointestinal tract. The route determines the absorption site and potential for first-pass metabolism. Gastrointestinal pH and surface area affect drug solubility and ionization state. Motility and emptying time influence drug contact with the mucosa. Food and disease can modify gastrointestinal conditions and blood flow, altering drug dissolution and permeability. These physiological factors must be considered for optimal drug bioavailability.

1. Physiological Factors Affecting Drug
bioavailability
presented by
M.pharm(2 sem)
Dept of pharmaceutics

2. • Physiological Factors Affecting Drug Absorption
(1) Routes of drug administration
(2) Membrane Physiology
i) Nature of cell membrane
ii) Transport processes
(3) pH and surface area of GIT
(4) Gastric emptying time.
(5) Gastrointestinal motility
(6) Splanchnic blood flow
(7) Drug stability in GIT
(8) Effect of food and nutrients
(9) Disease state
(10) Drug interaction

3. . Routes of Administration and Drug Absorption
• The route of administration (ROA) that is chosen has a large impact on how
fast the drug is taken up and how much of it arrives at its destination in an
active form.
• The route of administration is determined by the physical characteristics of the
drug, the speed at which the drug is absorbed, as well as the need to bypass
hepatic metabolism and achieve high conc. at particular sites
• Oral: Drug is taken orally.
• Features: Absorption takes place along the whole length of GIT (i.e. large
surface area)
• Absorption site: Gastrointestinal epithelia

4. • . Buccal/Sublingual: Drug is place in mouth or under tongue. Features: Rapid absorption
avoiding first-pass effect. Drugs which are highly lipid-soluble and subject to high first-pass
effect if swallowed are given through this route (e.g. Nitroglycerine)
• Absorption site: Buccal/ Sublingual mucosa
• Inhalation: The drug is inhaled and absorbed through the lungs Features: large surface
area and rapid absorption -Avoids first pass-metabolism.
• -Volatile and gaseous drugs are given in this route (e.g Absorption site: Alveoli of lung
• Intranasal: drug is given into the nasal cavity
• Absorption site: Nasal membrane
• Rectal: Drug is given into rectum e.g. suppositories
• Feature: absorption process avoids first-pass metabolism
• Absorption site: epithelia of rectal wall

5. • Parenteral routes: Biotechnology-derived drugs (e.g. insulin, erythropoietin,
somatotropin) are given through parenteral route because they are too labile
in GIT to be given orally.
• Intravenous (IV): placing a drug directly into the blood stream Features:
no absorption required, 100% bioavailable, rapid onset of action
Intramuscular (IM): drug injected into skeletal muscle; absorption is faster
then SC but slower than IV Absorption site: striated muscle fiber
Subcutaneous (SC): Absorption of drugs from the subcutaneous tissues
Absorption site: Subcutaneous tissue

6. . No single method of drug administration is ideal for all drugs in all
circumstances
The oral route is the most popular route of administration of drug because of
its-
• Large surface area for absorption
• Compartments with different pH that accommodate the drugs of different
solubility
• Convenient, easy and efficient route compared to other routes

7. • 2. Membrane physiology
•For systemic drug absorption drug molecules must cross the cell membrane
(oral route-intestinal epithelium). •Drug molecules may pass either
transcellular pathway or paracellular pathway. •The permeability of a drug at
the absorption site into systemic circulation depends on : -molecular structure
and properties of the drug. -physical and biochemical properties of cell
membrane. •So the biological membranes pose a significant barrier to drug
delivery.
i) Nature of cell membrane
ii) Transport processes

8. • . i Structure of cell membrane
• Cell membranes are generally thin,approximately 70 to 100 Å in thickness.
• Composed of primarily of phospholipids in the form of a bilayer interdispersed
with carbohydrates and protein groups.
• There are several theories as to the structure of cell membrane such as
Danielli-Davson model, Unit membrane model, Fluid mosaic model
. ii. Transport Process
Passage of drugs across cell membranes:
1.Passive diffusion.
2.Carrier mediated transport
• Active transport • Facilitated diffusion
3.Ion pair formation.
Others are: - Endocytosis -Exocytosis

10. • A. Passive diffusion
• Passive diffusion is the process by which molecules spontaneously diffuse
from a region of higher concentration to a region of lower concentration.
• It does not require energy.
• Drug molecule diffuses according to Fick’s law of diffusion:
dQ/dt= DAK (Cg-Cp)/ h
• Passive diffusion is the major absorption processes for most of the drugs.

11. • B.carrier mediatedTransport
• . Carriy a carrier present at the absorption site. •Numerous specialized carrier
mediated systems are present in the body especially in the intestine for the
absorption of ions and nutrients required by the body.
• •It is two types:
-Active transport (energy dependent).
-Facilitated diffusion(not energy dependent).

12. i. Active Transport
• Active transport requires a carrier molecule and a form of energy. The
energy is provided by the hydrolysis of adenosine tri phosphate. •Active
transport can transport a drug against a concentration gradient i.e. from
regions of low drug concentration to regions of high drug concentration.

13. • .Sodium, Potassium, Calcium ions, glucose, amino acids vitamins like niacin,
ascorbic acid are absorbed by this way.
• Drugs like methotrexate (anti cancer drug)-structurally similar to folic acid, 5-
fluorouracil (antineoplastic drug)- structurally similar to uracil are absorbed by
this way.
• Only a few drugs are absorbed by active transport mechanism.

14. i. Facilitated Diffusion
• Facilitated diffusion also requires a carrier molecule. But it does not require
energy.
• Here the drug moves along a concentration gradient.
• Some cephalosporin antibiotics such as cephalexin undergo facilitated
diffusion by an oligopeptide transporter protein located in intestinal epithelial
cells.

15. • C . Ion-Pair Formation
• Ion-pair formation is the main pathway for ionized drugs specially for which
maintain ionized state at any pH.
• These drugs penetrate the membrane poorly. So the charged drug forms a
complex with oppositely charged ligand and becomes neutral.
• This neutral complex can easily cross the absorption barrier by passive
diffusion.
• Ligand + drug→ ion-pair→ absorption barrier→ drug +ligand
• Ex: propranolol forms ion pair with oleic acid.

16. • D. Endocytosis
• In endocytosis membranes invaginate or pinch in to form a vesicle enclosed
the moving materials inside the cell.

17. • E. Exocytosis
• •Exocytosis is the process of a cell exporting material using vesicular
transport. Intracellular vesicle moves to the plasma membrane, where they
fuse with the membrane and release their contents into surrounding fluids.
•Cells of stomach and pancreatic cells secrete digestive enzymes through
exocytosis. •Certain neurotransmitters (such as nor-epinephrine) are stored
in membrane bound vesicles in the nerve terminal. They are released by
exocytosis.

18. • .21. pH AND SURFACE AREA OF
GIT

19. • ORAL CAVITY • Saliva is the main secretion of the oral cavity • pH 7 •
Contains ptyalin which digests starch. e.g fentanyl citrate, nitroglycerin etc
(lipid soluble drug)
• .ESOPHAGUS • It connects the pharynx and the cardiac orifice of stomach •
pH 5-6 • Very little drug dissolution occurs in it

20. • .. STOMACH • Fasting pH 2-6 • pH in presence of food is 1.5-2 • Intrinsic
factor enhances vit B-12 absorption & gastric enzymes initiate digestion •
Basic drugs are solubilized rapidly in presence of acid • pH may be increased
due to certain drugs e.g omeprazole • Ethanol easily crosses cell membrane
& efficiently absorbed from the stomach • e.g ibuprofen,aspirin etc absorbed
here

21. • INTESTINE • pH 5-8 • Large area for drug absorption • pH is
optimum for enzymatic digestion of protein and peptide containing
food. Hence protein type drug (e.g insulin) can’t be administered
orally • The influence of absorptive surface area is much
prominent than pH. • e.g vitamine,diazepam,quinidine etc absorb
here

22. • COLON AND RECTUM • pH 5.5-7 • Colon promotes melting of
oily drugs to form emulsion. • e.gIn crohn’s disease
prednisolone,hydrocortisone for infammatory bowel disease •
Rectums pH is 7 and virtually has no buffer capacity • Oral SRDF
are well absorbed in colon (e.g theophylline) • Suppositories are
well absorbed in rectum

23. IONIZATION of DRUG • Acidic drugs are absorbed faster in acidic
pH as they remain unionized in acidic medium of stomach. So they
can be absorbed through lipidic cell membrane.e.g aspirin
,ibuprofen • Basic drugs are not absorbed well in acidic pH because
they ionized in acidic medium. • Basic drugs remain unionize in
basic medium (small intestine) and can be easily absorbed.e.g
codein • Acidic drugs ionize in basic medium so can’t be absorbed. •
Highly acidic or basic drug ionize at all pH hence poorly absorbed in
GIT.e.g disodium cromogylate.guanethidine etc

24. • GASTRIC EMPTYING TIME • The time taken for stomach contents to be
passed into the duodenum influenced by gastric motility,activity of pyloric
sphincter etc • If acidic drugs remain for long time into stomach, they get
absorbed at a faster rate. • And if basic drug remains for a short time in
stomach and being more time in small intestine, they get easily absorbed. •
for acidic drug gastric emptying time should be more and for basic drug less.
• Example: penicillin is unstable in acid and decomposes if stomach emptying
is delayed. Other drugs, such as aspirin, may irritate the gastric mucosa
during prolonged contact.

25. • . FACTORS INFLUENCING GASTRIC EMPTYING TIME Factors Influence
on Gastric Emptying volume The larger the starting volume, the greater the
initial rate of emptying, after this initial period, the larger the original volume,
the slower the rate of emptying. Type of meal Reduction in rate of emptying
to an extent directly dependent upon concentration of carbohydrate,lipid and
protein type food Osmotic pressure Reduction in rate of emptying to an
extent dependent upon concentration for salts and nonelectrolytes Physical
state of gastric contents Solutions or suspensions of small particles empty
more rapidly Body position Rate of emptying is reduced in a patient lying on
left side. Viscosity Rate of emptying is greater for viscous solutions.

26. • . Contd. Factors influence on Gastric Emptying Emotional states Aggressive
or stressful emotional states increase stomach contractions and emptying
rate; depression reduces stomach contraction and emptying. Disease states
Rate of emptying is reduced in some diabetics and in patients with local
pyloric lesions and hypothyroidism; gastric emptying ratei s increased in
hyperthyroidism. drugs Anticholinergic,narcotic analgesic etc decrease
emptying

27. . GASTROINTESTINAL MOTILITY • It tends to move the drug
through the alimentary canal • This movement helps drug particle to
come in contact with mucosa and absorbed • The excessively rapid
movement of GIT impairs absorption.

28. • Gastrointestinal Motility Disorders • Achalasia • Gastroesophageal Reflux
Disease (GERD) • Functional chest pain • Gastroparesis / Delayed gastric
emptying • Rapid gastric emptying • Idiopathic vomiting / Cyclic vomiting
syndrome • Functional dyspepsia • Constipation • Diarrhoea • Irritable bowel
syndrome • Fecal incontinence

29. • . INTESTINAL MOTILITY • It mix the contents of the duodenum,
bringing them into intimate contact with the mucosal cells. • The
drug must have a sufficient time at the absorption site for optimum
absorption. • In case of high motility(e.g diarrhea) the drug has a
very brief residence time and less opportunity for adequate
absorption

30. • . Factors affecting intestinal motility a.Physical activity b.Food
c.Emotional condition d.Age, gender e.Disease state,drug etc It is
very important in absorption and bioavalability of SRDFs,enteric
coated dosage forms and drugs which are absorbed by carrier
mediated transport systems of small intestine.

31. • . Intestinal Motility Disorders • Intestinal pseudo-obstruction •
Irritable bowel syndrome • Fecal incontinence • Constipation

32. .SPLANCHNIC BLOOD FLOW • Some drugs are achieving higher
plasma conc. after food, this is because food increase splanchnic
blood flow. • e.g propranolol, chloramphenicol, lithium carbonate. •
The absorption of some drugs is reduced due to presence of food
(e.g ampicillin, aspirin, L-dopa) • In hypovalemic state, the
splanchnic blood flow is reduced. So absorption of the drug is also
decreased

33. • . DRUG STABILITY IN GIT • Metabolism or degradation by
enzymes or chemical hydrolysis may adversely affect the drug
absorption. • Destruction in gastric acid (e.g penicillin)

34. • . EFFECT OF FOOD • The presence of food in the GI tract affects
the bioavailability of oral drugs. • Some effects of food on the
bioavailability of the oral drugs include: • Delay in gastric emptying
time • Stimulation of bile flow • Change in the pH of GI tract •
Increase in splanchnic blood flow • Change in luminal metabolism
of drug substances • Physical/chemical interaction of metal with
drug substances

35. • . Contd. • The nutrient and caloric contents of the meal, meal
volume, meal temperature etc affect drug product transit time,
luminal dissolution, drug permeability and systemic availability.
Thus it affects drug absorption. • Absorption of some antibiotics
decreases when administered with food (e.g. penicillin,
tetracycline)

36. • Contd. • Absorption of some lipid soluble drugs increases when
administered with food. e.g. metazalone. • The presence of food
in the GI lumen stimulates the flow of bile which increases the
solubility of fat soluble drugs by forming micelle. • The presence of
food in the stomach lowers the pH which causes rapid dissolution
and absorption of basic drugs with limited aqueous solubility. e.g.
cinnarizine

37. • Contd. • Drugs irritating to GI mucosa (e.g: erythromycin, aspirin,
NSAIDs etc) given with food to reduce the irritation by decreasing
the rate of drug absorption. • In the presence of food, enteric
coated and non disintegrating drug products can not reach the
duodenum rapidly, thus they delay drug release & systemic drug
absorption.

38. • . Contd. • Food can also affect the integrity of dosage form which
causes an alteration in the release rate of the drug. e.g.
theophylline. • Timing of drug administration is important as taking
a medication either 1 hr before or 2 hr after meals , avoid any
delay in drug absorption.

39. • . Effect of nutrients on drug absorption • Absorption of water
soluble vitamins (e.g. B- 12, folic acid) in the stomach are
facilitated by forming complex with intrinsic factors. • Absorption of
calcium in the duodenum is facilitated by vita-D by increasing
calcium binding protein which binds calcium in the intestinal cell &
transfer it to the blood circulation.

40. • . Contd. • Grape juice contains various flavonoids e.g. naringin
which inhibits cytochrome P-450 enzymes . Thus it inhibits
absorption of some drugs.

41. • EFFECT OF DISEASE STATES • Drug absorption differs in any
disease which causes changes in – • 1. Intestinal blood flow •
2.Gastrointestinal motility • 3.Changes in stomach emptying time •
4.Gastric Ph • 5.Intestinal pH • 6. Permeability of gut wall • 7. Bile
secretion • 8.Digestive enzyme secretion • 9.Alteration of normal
GI flora

42. • . Contd. • Patient with Parkinson’s disease have difficulty
swallowing & greatly diminished GI motility • Patient on tricyclic
antidepressants & antipsychotic drugs reduce GI motility which
delay drug absorption • In achlorhydric patient weak-base drugs
remain undissolved in stomach because no adequate acid e.g.
Dapsone

43. • . Contd. • In patient with acid reflux disorder ,PPI such as
omeprazole , render stomach achlorhydric, may affect drug
absorption • HIV-AIDS patients are prone to a number of GI
disturbances e.g. increased gastric transit time, diarrhea • CHF
patient with persistent edema reduce blood flow to the intestine &
intestinal motility results in decrease absorption e.g. furosemide

44. • . Contd. • Crohn’s disease causes impaired absorption due to
reduce surface area & thicker gut wall e.g. higher plasma
propranolol conc. observe in crohn’s
• .
• .permeability of small intestine • Cephalexin absorption increase
in Celiac disease

45. • DRUGS THAT AFFECT ABSORPTION OF OTHER DRUGS •
Metoclopramide stimulates stomach contrac tion & increases
intestinal peristals • Decrease the peak drug conc. by reducing
effective time for absorption • For example, digoxin absorption is
reduced by metoclopramide but increased by propantheline
bromide

46. • Contd. • Anticholinergic drug (propantheline bromide) may slow
stomach emptying &motility of small intestine • Tricyclic
antidepressants & phenothiazines with anticholinergic side effects
cause slower peristalsis & stomach emptying may delay in drug
absorption • Antacid not given with cimetidine,tetracycline
because reduce absorption

47. • . Contd. • PPI e.g. omeprazole rais gastric pH • Interfere with
drugs for which gastric pH affects bioavailability (e.g.ampicillin)&
enteric- coated drug product (e.g. aspirin) • Cholestyramine is a
nonabsorbable ion- exchange resin for the treatment of
hyperlipemia • It binds warfarin,thyroxine,thereby reducing
absorption of these drugs.

48. • . Contd. • Erythromycin inhibits the hepatic metabolism of a
number of drugs e.g. Digoxin. • Antibiotic eliminates a species of
intestinal flora that inactivates digoxin,thus leading to greater
reabsorption of drug from the enterohepatic circulation.