Pharmacokinetics / Biopharmaceutics - physiological factors affecting oral absorption

1. Physiological Factors Affecting
Oral Absorption
The ultimate goal of PK is to have the drug reach the site
of action in a concentration which produces a
pharmacological effect. No matter how the drug is given
(other than IV) it must pass through a number of
biological membranes before it reaches the site of action.

2. Pharmacokinetics of Drug Absorption
• The systemic drug absorption from the
gastrointestinal (GI) tract or from any other
extravascular site is dependent on:
1) The physicochemical properties of the drug.
2) The dosage form used.
3) The anatomy and physiology of the absorption
site.

3. Factors Affecting Absorption
• Formulation factors
–Tablet disintegration
–Inert ingredient /
solvent effects
–Solubility
–Drug pka
–Concentration
• Patient factors
–Absorbing surface
–Blood flow
–pH
–Disease states
–Interactions with
food, other drugs

4. The physicochemical properties of the drug
• pH - partition theory
– For a drug to cross a membrane barrier it must normally
be soluble in the lipid material of the membrane to get
into membrane, also it has to be soluble in the aqueous
phase as well to get out of the membrane.
– Most drugs have polar and non-polar characteristics or
are weak acids or bases.
– For drugs which are weak acids or bases the pKa of the
drug and the pH of the GI tract fluid and the pH of the
blood stream will control the solubility of the drug and
thereby the rate of absorption through the membranes,
lining the GI tract.

5. Formulation factors
• A drug must be in solution to be absorbed from
the GI tract.
• The bioavailability of a drug decrease in the
order:
solution > suspension > capsule > tablet > coated tablet
This order may not always be followed but it is a
useful guide.

6. Pharmacokinetics of Drug Absorption
• For oral dosing, such factors affect the rate
and the extent of drug absorption:
i. surface area of the GI tract.
ii. stomach-emptying rate.
iii. GI mobility.
iv. blood flow to the absorption site.

7. pH Membrane Blood Supply Surface Area Transit Time By-pass liver
BUCCAL approx 7 thin Good, fast
absorption
with low dose
small Short unless
controlled
yes
ESOPHAGUS 5 - 6 Very thick, no
absorption
- small short -
STOMACH 1 - 3
decomposition,
weak acid
unionized
normal good small 30 - 40
minutes,
reduced
absorption
no
DUODENUM 6 - 6.5 bile
duct,
surfactant
properties
normal good very large very short (6"
long), window
effect
no
SMALL
INTESTINE
7 - 8 normal good very large 10 -
14 ft, 80 cm 2
/cm
about 3 hours no
LARGE
INTESTINE
5.5 - 7 - good not very large 4
- 5 ft
long, up to 24
hr
rectum yes
GI Physiology and Drug Absorption

11. Gastric emptying and motility
• Generally drugs are better absorbed in the small
intestine (because of the larger surface area) than in
the stomach, therefore increasing stomach emptying
will increase drug absorption.
• The quicker the stomach emptying the higher the
plasma concentration.
• Also slow stomach emptying can cause increased
degradation of drugs in the stomach's lower pH; e.g.
L-dopa.

12. Food
• Food can effect the rate of gastric emptying.
• For example fatty food can slow gastric emptying
and retard drug absorption. Generally the extent
of absorption is not greatly reduced.
• Occasionally absorption may be improved.
Griseofulvin absorption is improved by the
presence of fatty food. Apparently the poorly
soluble griseofulvin is dissolved in the fat and
then more readily absorbed.

13. • Propranolol plasma concentrations are larger
after food than in fasted subjects. This may be
an interaction with components of the food.
The Effect of Fasting versus Fed on Propranolol Concentrations

14. Passage of Drugs across Biological membrane
• Transport across the membranes
Transcellular transport
 Passive diffusion
 Carrier-mediated transport
 Facilitated diffusion
 Active transport
 Ion-pair transport
 Endocytosis or
Pinocytosis
Paracellular transport
 Bulk flow
 Filtration

15. Transcellular transport
 Passive diffusion
 Most (many) drugs cross biologic membranes by passive
diffusion.
 Diffusion occurs when the drug concentration on one side of
the membrane is higher than that on the other side. Drug
diffuses across the membrane in an attempt to equalize the
drug concentration on both sides of the membrane.
 Drugs that can passively diffuse through cell membrane
must be:
• Lipid soluble
• Unionized form
• Move according to concentration gradient

17.  Carrier-mediated transport
1. Facilitated diffusion
Carrier needed
Can be saturated
No energy required
Move along conc. Gradient
e.g. vitamin B12 transport.
2. Active transport
Carrier needed
Can be saturated
Energy required
Move against conc. Gradient
competitive inhibition is possible
E.g. glucose and amino acids

18. 3. Carrier-mediated intestinal transport (P-gp)
• P-glycoprotein (P-gp, MDR-1) is a 170 kDa membrane-bound
protein.
• P-gp transporters are present throughout the body including liver,
brain, kidney and the intestinal tract epithelia.
• This is an active, ATP-dependent process which can have a
significant effect on drug bioavailability.
• They appear to be an important component of drug absorption
acting as reverse pumps generally inhibiting absorption. They
work as efflux transporters and provide a defense mechanism
against harmful substances. They transport certain hydrophobic
substances in the following direction:
 Into the gut
 Out of the brain
 Into bile
 Into urine
 Out of the gonads
 Out of other organs

19. • P-glycoprotein works against a range of drugs such as cyclosporin
A, digoxin, β-blockers, antibiotics and others. This process has
been described as multi-drug resistance (MDR).
• Additionally P-glycoprotein has many substrates in common with
cytochrome P450 3A4 (CYP 3A4) thus it appears that this system
not only transports drug into the lumen but causes the metabolism
of substantial amounts of the drug as well (e.g. cyclosporin).
• Clinically significant substrates of P-gp include digoxin,
cyclosporine, fexofenadine, paclitaxel, nortriptyline and
phenytoin.
• A number of compounds can act as P-gp inhibitors including
atorvastatin, ketoconazole or erythromycin (digoxin AUC
increased) and grapefruit juice (increased paclitaxel absorption).
• Rifampin has been reported to induce P-gp expression.

20.  Vesicular Transport
Pinocytosis and phagocytosis
Macromolecules are
transported by
endocytosis or
exocytosis
e.g. Vitamin A, D, E,
and K,
 Ion-pair transport
e.g. Propranolol and Quinine
For example, the formation of ion pairs
to facilitate drug absorption has been
demonstrated for propranolol, a basic
drug that forms an ion pair with oleic
acid

21. Paracellular Transport
Pore (convective) Transport
Bulk flow and Filtration
• Very small molecules (such as urea, water, and
sugars) are able to cross cell membranes rapidly,
as if the membrane contained channels or pores.
• Filtration is an important way to excrete drugs

22. Passage of Drugs across Biological membrane
• Drug properties
 Molecular weight, shape and size
 Small molecules – more chance of crossing
membrane

23. Passage of Drugs across Biological membrane
• Lipid solubility
• Movement directly through the lipid bilayer
requires that the substance dissolve into the lipid
bilayer
Increase lipid solubility causes increased partition coefficient
Increase in partition coefficient causes increased permeability.
Permeability
Kp

24. Ionization
General rules
 A drug usually exists in 2 forms – unionized and ionized
forms.
 Unionized drug can passively diffuse across membrane
 The ratio of unionized drug will indicate direction of
passive diffusion
 Factors affecting ionization are
 pH of the medium
 pKa (acid dissociation constant) of the drug
 Acidic drug tend to ionize in more basic medium
 pH – pKa = log (ionized / nonionzized)
 Basic drug tend to ionize in more acidic medium
 pH – pKa = log (nonionized / ionized)24

25. Ionization
• Henderson-Hasselbach Equations for calculations
pH = pK + log [H+ acceptor]
[H+ donor]
25

26. Stomach fluid
pH 2
Plasma
pH 7
More non-ionized Ionized
Less non-ionized Ionized
Example
Acidic drug pKa 6 pH – pKa = log (ionized / non-ionized)
26

27. Some data for practice calculation
pH
Plasma 7.4
CSF 7.4
Stomach 1.4
Small Intestine 8.0
Acidic drug pKa Basic drug pKa
Ampicillin 2.5 Strychnine 8.0
Sulfadiazine 6.5 Aminopyrine 5.0
Aspirin 3.4 Procaine 9.0
27

28. Routes of Drug Administration
• The route of administration (ROA) that is chosen may
have a profound effect upon the speed and efficiency
with which the drug acts.
• Appropriate administration route depends on:
 the dosage form in which the drug is available
 the patient’s age
 the patient’s condition, e.g. level of consciousness

29. Sublingual/buccal
• Some drugs are taken as smaller tablets which are held in the
mouth or under the tongue.
• Advantages:
 rapid absorption
 drug stability
 avoid first-pass effect
 Ideal for lipid soluble drugs
 Absorption favored of acids with high pka and bases with low pka
• Disadvantages
 inconvenient
 small doses
 unpleasant taste of some drugs

30. Rectal
• Advantages:
 unconscious patients and children
 if patient is nauseous or vomiting
 Bypassing first pass effect (partially)
 good for drugs affecting the bowel such as laxatives
• Disadvantages
 absorption may be variable
 irritating drugs contraindicated
 discomfort

31. Intravenous (IV)
• Advantages:
 complete bioavailability
 precise, accurate and almost immediate onset of action,
 large quantities can be given, fairly pain free
• Disadvantages
 greater risk of adverse effects
 high concentration attained rapidly (anaphylaxis)
 risk of embolism
 Cost
 Drug suspensions cannot be used

32.  Subcutaneous
 slow and constant absorption
 absorption is limited by
blood flow, affected if
circulatory problems exist
 concurrent administration
of vasoconstrictor will slow
absorption
 Intramuscular
 rapid absorption of drugs in aqueous solution
 depot and slow release preparations
 pain at injection sites for certain drugs

33. Inhalation
• Gaseous and volatile drugs may be inhaled and absorbed
by the pulmonary epithelium and mucous membranes of
respiratory tract.
-almost instantaneous absorption,
-large surface area of alveoli (~72 m2)
-high permeability of alveolar membrane
-avoids first-pass metabolism
• Local application (mainly)
• Difficulties in regulating the exact amount of dosage.
• Sometimes patient having difficulties in giving
themselves a drug by inhaler.

34. Oral Administration
• Advantages:
 Generally the safest route
 Convenient - can be self- administered, pain free, easy
to take
 Absorption - takes place along the whole length of the
GI tract
 Cheap - compared to most other parenteral routes
 No need for sterile equipment
 Variety: tablets, capsules, fast, slow release …..

35. Oral Administration
• Disadvantages
 Sometimes inefficient - only part of the drug may be
absorbed.
 First-pass effect - drugs absorbed orally are initially
transported to the liver via the portal vein
 Irritation to gastric mucosa - nausea and vomiting
 Destruction of drugs by gastric acid and digestive juices, gut
flora, mucosal enzymes
 Onset of effect is slow
 unpleasant taste of some drugs
 unable to use in unconscious patient
 Food interaction and G-I motility can affect drug absorption

40. Physiological Factors
– Gastric motility
– Gastric emptying time
– pH at the absorption site
– Area of absorbing surface
– Blood flow
– Disease states
– Ingestion with or without food
40

41. Oral drug absorption
Oral cavity:
Saliva is the main secretion (1500
mL/day)
Saliva contains amylases
The pH is 6-7
Highly vascular area
Esophagus:
pH of 5-6
No drug absorption from this site
Very little dissolution

42.  Stomach :
 The surface area for absorption of drugs is relatively
small in the stomach due to the absence of macrovilli &
microvilli.
 Extent of drug absorption is affected by variation in the
time it takes the stomach to empty, i.e., how long the
dosage form is able to reside in stomach.
 Drugs which are acid labile must not be in contact with
the acidic environment of the stomach.
 pH of 1.5 -2 (fed-state) or 2 – 6 (fasted-state).
 HCl secretion of the stomach is stimulated by gastrin and
histamine.
 High-density foods generally are emptied from stomach
more slowly.

43. Small Intestine:
 Include duodenum, jejunum and ileum.
 Major site for absorption of most drugs due to its large
surface area.
 The Folds in small intestine called as folds of kerckring,
result in 3 fold increase in surface area.
 These folds possess finger like projections called Villi
which increase the surface area 30 times.
 From the surface of villi protrude several microvilli which
increase the surface area 600 times.
 Blood flow is 6-10 times that of
stomach.
 pH Range is 6–7.5 , favorable
for most drugs to remain unionised.

44. Small Intestine:
 Peristaltic movement is slow, while transit time is long.
 Permeability is high.
 The drugs which are predominantly absorbed through the
small intestine, the transit time of a dosage form is the major
determinant of extent of absorption.
 the transit time in small intestine for most healthy adults is
between 3 to 4 hours, and a drug may take about 4 to 8 hours
to pass through the stomach & small intestine during fasting
state.
 During the fed state, the small intestine transit time may take
about 8 to 12 hours.

45. Large intestine:
Include colon and rectum
Lack villi
Limited absorption from colon
The major function of large intestine is to absorb
water from ingestible food residues which are
delivered to the large intestine in a fluid state, &
eliminate them from the body as semi solid feces.
pH ranging from 5.5-7
Colon contains microorganisms
Only a few drugs are absorbed in this region.

46. Influence of drug pKa and GI pH on
drug absorption
Drugs Site of absorption
Very weak acids (pKa > 8.0) Unionized at all pH values
Absorbed along entire length of GIT
Moderately weak acids (pKa 2.5 – 7.5) Unionized in gastric pH
Ionized in intestinal pH
Better absorbed from stomach
Strong acids (pKa <2.5) Ionized at all pH values
Poorly absorbed from GIT
Very weak bases (pKa < 5) Unionized at all pH values
Absorbed along entire length of GIT
Moderately weak bases (pKa 5 – 11 ) Ionized in gastric pH
Unionized in intestinal pH
Better absorbed from intestine
Strong bases (pKa >11) Ionized at all pH values
Poorly Absorbed from GIT

47. GIT motility and Gastric Emptying
• GI motility tends to move the drug through the
alimentary canal.
• For each drug there is an optimal absorption
window.
• Physiologic movement of drug within the GIT
depends on fed/fasted state.
• The time a dosage form takes to leave the
stomach is usually termed: the gastric
residence time, gastric emptying time.

48. • Rapid Gastric Emptying Advisable when :
– Rapid onset of action is desired eg. Sedatives
– Dissolution occurs in the intestine eg. Enteric coated tablets
– Drugs not stable in GI fluids eg. penicillin G
– Drug is best absorbed from small intestine eg. Vitamin B12
• Delay in Gastric Emptying recommended when
– Food promotes drug dissolution and absorption e.g.
Gresiofulvin
– Disintegration and dissolution is promoted by gastric fluids

49. Factors affecting Gastric Emptying
Volume of Ingested
Material
Bulky material tends to empty more slowly than
liquids
Type of Meal Gastric emptying rate:
carbohydrates > proteins > fats
Temperature of Food Increase in temperature, increase in emptying rate
Body Position Lying on the left side decreases emptying rate and right
side promotes it
GIT pH Retarded at low stomach pH and promoted at higher
alkaline pH
Emotional state Anxiety and stress promotes where as depression retards
it
Disease states gastric ulcer, diabetes and hypothyroidism retards it,
while duodenal ulcer, hyperthyroidism promotes it.

50. Effect of Food:
- The presence of food in the GIT can influence the rate
and extent of absorption, either directly or indirectly
via a range of mechanisms.
- As a general rule, drugs are better absorbed under
fasting conditions. Presence of food may retard or
prevent drug absorption.
- Generally the extent of absorption is not greatly
reduced. Occasionally absorption may be improved
- Food does not significantly influence absorption of a
drug taken half an hour or more before meals and two
hours or more after meals.

51. Effect of Food:
• Increased drug absorption following a meal
can be due to the following reasons:
a) Increased time for dissolution of poorly soluble drug.
b) Enhanced solubility due to GI secretions like bile.
c) Prolonged residence time and absorption site contact of
the drug e.g. water-soluble vitamins.

52. Effect of Food:
• Delayed or decrease drug absorption by food
can be due to one or more of the following
reasons:
a) Delayed gastric emptying, affecting the drugs unstable in the stomach
e.g. penicillin, erythromycin.
b) Preventing the transit of enteric tablets into the intestine which may be
as long as 6 – 8 hrs.
c) Formation of poorly soluble, unabsorbable complex e.g. tetracycline-
calcium complex.
d) Alteration of pH
e) Competition between food components and drugs for specialized
absorption mechanisms

53. Effect of Food:
• Types of meal
a) Meals high in fat aid solubilisation of poorly aqueous soluble
drugs like griseofulvin.
b) Food high in proteins increases oral availability of propranolol
because
 such a meal promotes blood flow to the GIT helping in drug
absorption.
 increases hepatic blood flow due to which the drug can bypass
first-pass hepatic metabolism (propranolol is a drug with high
hepatic metabolism)

54. Effect of Fasting versus Fed on Metaxalone
Concentrations

55. A comparison of the effects of different types of food
intake on the serum griseofulvin levels following 1.0
g oral dose

56. Effect of water volume and meal on the
bioavailability of some drugs
F aspirin (650-mg) tablets,
erythromycin stearate (500-
mg) tablets, amoxicillin
(500-mg) capsules, and
theophylline (260-mg)
tablets, together with large
and small accompanying
volumes of water.

57. Theophylline serum concentrations in an
individual subject after a single 1500 mg Theo-24
Theophylline serum
concentrations in an individual
subject after a single 1500-mg
dose of Theo-24 taken during
fasting and after breakfast. The
shaded area indicates the
period during which this
patient experienced nausea,
repeated vomiting, or severe
throbbing headache. The
pattern of drug release during
the food regimen is consistent
with "dose dumping."