UNIT IV

FACTORS AFFECTING DRUG

ABSORPTION
Vermont e. Arvesu, rph

Physiologic Factors Affecting Absorption

A.

Membrane Physiology
Membrane structure

Complex: composed of lipids, CHONs, lipoproteins and

polysaccharides
Semi-permeable membrane
- permits the rapid passage of some chemicals while
retarding or preventing passage of others
- Lipid-soluble, unionized, nonpolar, low MW can cross
easily
- Ionic, polar, CHONs, CHON-bound drug and
macromolecules cannot cross easily

Physiologic Factors Affecting Absorption

A.

Membrane Physiology
Membrane structure

Dynamic lipoid sieve

- carrier molecules shuttle back and forth across the
membranes through microscopic aqueous pores or
channels

Physiologic Factors Affecting Absorption

Membrane Physiology
Examples of Membrane Types
1. Blood Brain Barrier
A.

Effectively no pores
Prevents many polar materials from entering the brain
Smaller lipid materials or lipid soluble materials, general
anesthetics such as diethyl ether, halothane, can easily cross

Physiologic Factors Affecting Absorption

Membrane Physiology
Examples of Membrane Types
2. Renal tubules
A.

Relatively nonporous
Reabsorption (lipid compounds or non-ionized species
dependent on pH and pKa)

3. Blood capillaries and renal glomerular membranes

Quite porous
Allow non-polar and polar molecules to pass through

Physiologic Factors Affecting Absorption

B. Transport processes across the membranes
1.
Passive diffusion

Transfer occurs from a region of higher concentration to a

region of lower concentration
Involves the successive partitioning of a solute between
aqueous and lipid phases as well as diffusion within the
respective phases
Ficks Law of Diffusion

rate of diffusion across a membrane is proportional to the

difference in drug concentration on each side of the
membrane

Physiologic Factors Affecting Absorption

B. Transport processes across the membranes
1.
Passive diffusion

Ficks Law of Diffusion

dq = DAK (C1-C2)
dt
h

where:
dq/dt = rate of drug diffusion
C1 = conc. of drug in compartment one
D = diffusion rate constant
C2 = conc. of drug in compartment two
A = surface area of absorbing surface
K = lipid-water partition coefficient
h = thickness of membrane

Physiologic Factors Affecting Absorption

B. Transport processes across the membranes
2. Carrier-mediated Transport
Carriers in the lipoprotein membranes of the intestinal
epithelial cells shuttle solutes from the mucosa to the serosa

Selective, competitive, saturable

Types
a.
Active
Transports uphill against a concentration or an
electrochemical potential gradient
Requires energy

Physiologic Factors Affecting Absorption

B. Transport processes across the membranes
2. Carrier-mediated Transport
Types
a.

Active

transfer of polar molecules, glucose, amino acids

thiamine, niacin, riboflavin, vitamin B6, methyldopa, 5-fluorouracil

b.

Facilitated

Transports downhill against a concentration gradient

Does not require energy

Vitamin B12

Physiologic Factors Affecting Absorption

B. Transport processes across the membranes
3. Pore/Convective/Paracellular Transport

Transport across tight or narrow junctions between cells

(transendothelial channels)
Involves both diffusion and the convective (bulk) flow of water
and accompanying water-soluble drug molecules through the
channels (shifting of solvent)

Physiologic Factors Affecting Absorption

B. Transport processes across the membranes
4. Vesicular Transport
Process of engulfing particles or dissolved materials by a cell

Does not require a drug to be in aqueous solution

Types
a.
Pinocytosis
Cell drinking
Engulfment of small solute or fluid volumes
Vitamins ADEK

Physiologic Factors Affecting Absorption

B. Transport processes across the membranes
4. Vesicular Transport
Types
b. Phagocytosis
Cell eating
Engulfment of larger particles (macromolecules), generally by
macrophages
c. Endocytosis
Movement of particles into the cell
d. Exocytosis
- Movement of particles out of the cell

Physiologic Factors Affecting Absorption

B. Transport processes across the membranes
5. Ion-pair Formation

Drugs link up with an oppositely charged ion forming a neutral

molecule which diffuses easily across membranes
Quaternary ammonium compounds

6. Transporters proteins

p-glycoprotein
ATP-dependent pumps which aid the efflux of drug molecules from
the cell
Cyclosporine, nifedipine, digoxin

Physiologic Factors Affecting Absorption

C. Gastrointestinal physiology
Major components
1.
Stomach
2.
Small intestine
a.
Duodenum
b.
Jejunum
c.
Ileum
3. Large intestine or colon

Physiologic Factors Affecting Absorption

C. Gastrointestinal physiology

1.
-

Major segments of the GIT differ from

one another anatomically and
morphologically
Stomach
pouch-like structure lined with a
relatively smooth epithelial surface
Extensive absorption of weakly acidic or
nonionized drugs and certain weakly
basic drugs (alcohol, barbital)

Physiologic Factors Affecting Absorption

C. Gastrointestinal physiology
2. Small intestine
-

Most important site for drug absorption in the GIT

(duodenum)
Epithelial surface area is extraordinarily large (villi and
microvilli)
Most important region of the GIT with respect to carriermediated transport
Proximal small intestine is the major area for absorption
of dietary constituents including monosaccharides, amino
acids, vitamins and minerals
Vit B12 and bile salts appear to have specific sites in the
ileum

Physiologic Factors Affecting Absorption

C. Gastrointestinal physiology
3. Large intestine
- less irregular mucosa than small intestine
Reserve area for the absorption of drugs
that have escaped absorption because of
their physicochemical properties of their
dosage form
- Efficacy of orally administered drugs, such
as sulfasalazine, that require metabolism by
intestinal bacteria in the ileum and colon for
bioactivation

Physiologic Factors Affecting Absorption

C. Gastrointestinal physiology

Gastrointestinal Blood Flow

Network of capillaries and lymphatic vessels
Increase in mesenteric blood flow will increase drug absorption
Gastrointestinal pH
pH of body fluids: stomach (1), lumen of intestine (6.6), blood
plasma (7.4)
Degree of ionization
Type of dosage form
Route of administration

Physiologic Factors Affecting Absorption

C. Gastrointestinal physiology
Gastric Emptying and Gastrointestinal motility
Gastric emptying time: 2-4 hours
Gastrointestinal transit time: 4-10 hours
The quicker the stomach emptying, the higher the plasma
concentration for drugs that are prone to acid and gastric
enzyme degradation and for those that are absorbed in the
intestine

E.g. Penicillins, erythromycin and L-dopa

Slow gastric emptying is favorable for drugs that are

absorbed in the stomach

Physiologic Factors Affecting Absorption

Factors affecting Gastric Emptying
FACTORS

END RESULTS

1. Volume of
ingested materials

As volume increases, initially an increase in GE

then a decrease
Bulky materials empty more slowly than liquids
and small particles (<1 mm)

2. Type of Meal

Fatty food decrease

CHO decrease
Increase in temp = decrease

3. Body position

standing = increase
lying = decrease
lying on the left side = decrease

Physiologic Factors Affecting Absorption

Factors affecting Gastric Emptying
FACTORS

END RESULTS

4. Emotional State

aggressive, stress = increase

depression = decrease

5. Age

elderly = decrease

6. Exercise

decrease

7. Disease state

Hyperthyroidism = increase

8. Drugs

Anticholinergics, narcotics, analgesics

decrease
laxatives = increase

Physiologic Factors Affecting Absorption

D. Food

Generally, food retards transit

Generally, better absorption in fasted
state and with a larger volume of
water
NOT always predictable

Decrease absorption for penicillin,

tetracycline, erythromycin
Increase absorption for griseofulvin in
presence of fat
Increase absorption for cinnarizine,
lovastatin

Physiologic Factors Affecting Absorption

E. Microbial Flora

Aerobic and anaerobic

microorganisms may metabolize
some drugs (L-dopa and lactulose)
Clindamycin and propranolol
absorption are increased in the
presence of anaerobes

Formulation Factors Affecting Absorption

A.

Drug Solubility

Static (equilibrium) property in a saturated solution

Drug Dissolution

Rate limiting step for most drugs

Where:

Noyes Whitney Equation

dm

= DA (Cs
Cb)
dt
h

dm/dt = rate of drug dissolution

D = diffusion rate constant
A = surface area
h = thickness of stagnant layer
Cs = conc. of drug in
stagnant/diffusion layer
Cb = conc. of drug in bulk sovent

Formulation Factors Affecting Absorption

B. Particle Size

Inversely related to surface area

Dissolution rate directly related to surface area
Theophylline, griseofulvin, sulfisoxazole
Micronization (5 microns or less
For hydrophobic drugs: excessive particle size reduction
does NOT always lead to faster dissolution rate due to
formation of aggregates

Formulation Factors Affecting Absorption

C. Partition coefficient

Ratio of drug solubility (at equilibrium) in a nonaqueous

solvent (n-octanol) and aqueous solvent (water, pH 7 and
buffer solutions)
Hydophilic drugs with higher water solubility have a
faster dissolution rate than hydrophobic or lipophilic
drugs
The greater the affinity of a drug for lipid and the more
hydrophobic it is, the faster will be its rate of penetration
into the lipid rich membrane

Formulation Factors Affecting Absorption

D. Degree of ionization

Dependent on the pKa of weak electrolyte and the pH of

the solution
Most drugs are weak organic acids or bases
Cell membranes are more permeable to nonionized
forms

Greater lipid solubility of the nonionized form

Highly charged nature of the cell membrane
Hydration of ions resulting to larger particles

Formulation Factors Affecting Absorption

D. Degree of ionization
Henderson-Hasselbalch Equation
Weak acid:
pH = pKa + log
ionized conc (salt)
nonionized conc (acid)
Weak base:
pH = pKa + log
non-ionized conc (base)
ionized conc (salt)

Formulation Factors Affecting Absorption

D. Degree of ionization

If pH = pKa, there are equal amounts of ionized and nonionized species

Phenobarbital (pKa = 7.4) when placed in plasma (pH = 7.4)

will have equal amounts of ionized and nonionized forms. In
the stomach (pH = 1) it will be largely nonionized and will be
more absorbed
favorable pH: weak acids when pH <pKa, weak bases when
pH >pKa

Formulation Factors Affecting Absorption

E. Chemical Variation

Salt formation, ester formation

To provide slower dissolution, slower absorption and longer
duration of action
Selected for greater stability, less local irritation at the
absorption site or less systemic toxicity
Na aspirin is more soluble but less stable than aspirin

Weak acids: water-soluble forms are K+ and Na+ salts

Weak base: water-soluble forms are HCl, SO4 , citrate, gluconate

Aminophylline (ethylenediamine salt of theophylline) is 5x more

water soluble

Formulation Factors Affecting Absorption

F. Polymorphism

Ability of drug to exist in more than one crystalline forms

Different polymorphs have different physical properties

Crystalline definite identifiable shape

Amorphous no definite structure
Crystalline Novobiocin, chloramphenicol palmitate inactive
Crystalline K or Na Penicillin G more stable

Amorphous is more soluble than crystalline

Amorphous insulin rapid absorption IM/SQ

Crystalline insulin for long duration
70% crystalline and 30% amorphous for intermediate action

Formulation Factors Affecting Absorption

F. Polymorphism

Metastable fom is more soluble but less resistant to chemical

degradation than the stable form

G. Chirality

Ability of the drug to exist as optically active stereoisomers or

enantiomers
Each enantiomer behave differently pharmacokinetically and
pharmacodynamically
Most chiral drugs are used as RACEMIC mixtures

Ibuprofen exist as R- and S- enantiomers with S- as the

pharmacologically active. R- undergoes presystemc inversion in the
gut to S-

Formulation Factors Affecting Absorption

H. Hydrates

Affects dissolution rate

Hydrated or solvated drugs added with water or an
organic solvent , respectively
Anhydrous is more soluble than hydrated

Anhydrous ampicillin dissolves faster than trihydrate ampicillin

Formulation Factors Affecting Absorption

I. Complex Formation

Reversible or irreversible association of two or more

interacting molecules or ions

A chelate is a complex that typically involves a ring-like

structure formed by the interaction between a partial ring of
atoms and a metal

Usually alters physical and chemical characteristics of a

drug

Tetracycline Ca+2 complexes are poorly absorbed

Drug-cyclodextrin complexes are more water-soluble

Drug-protein complexes do not cross cell membranes
easily

Dosage Form Factors Affecting Absorption

A.

1.
2.
3.
4.
5.
6.
7.
8.

Role of the Dosage Form in GI Absorption

Design of the appropriate dosage form or delivery system
depends on
Physical and chemical properties of the drug
Dose of the drug
Route of administration
Type of drug delivery system desired
Desired therapeutic effect
Physiologic release of the drug from the delivery system
Availability of the drug at the absorption site
Pharmacokinetics and pharmacodynamics of the drug

Dosage Form Factors Affecting Absorption

The more complicated the formulation of the finished drug
product the greater the potential for absorption problem

Absorption of the drug from an oral solid dosage form depends

on a succession of processes
Liberation
(Attrition, Disintegration, Disaggregation)

Dissolution
Convection and Diffusion

Absorption

Dosage Form Factors Affecting Absorption

Rate-limiting step in the absorption of the drug is the slowest

step in the series of processes

Conventional oral dosage forms dissolution

Modified-release forms liberation

SOLUTIONS

Absorption is rapid and complete

Rate limiting step is the rate of gastric emptying

A drug in hydroalcoholic solutions has good absoption but may

tend to form finely divided precipitates in the lumen of GIT

Viscosity may interefere with dilution and mixing with GIT

contents

Dosage Form Factors Affecting Absorption

EMULSIONS

Inherently unstable (droplets tend to coalesce)

Emulsifier prevents coalescence and maintains the integrity of the

individual droplets
SUSPENSIONS

Finely divided powder will maximize the potential for rapid

dissolution due to a large surface area

Surface active agent will improve the dispersion of a suspension

and may improve the absorption of very fine particles

High viscosity, prolongs gastric emptying time, slow drug

dissolution and decrease the absorption rate

Dosage Form Factors Affecting Absorption

CAPSULES
A.
Hard capsule

Usually filled with a powder blend

Contents should not be subjected to high

compression forces

Dispersing agent will minimize

aggregation and maximize the surface
area of the powder

Should disrupt rapidly and allow the

contents to mix with GIT contents

Dosage Form Factors Affecting Absorption

CAPSULES
A.
Hard capsule

Affected by
- excipients
- method of manufacture
- aging and storage
At low RH, become brittle
At high RH, become moist, soft and
distorted

Moisture transferred to the capsule

contents
Problem is compounded when the contents
are also hygroscopic

Dosage Form Factors Affecting Absorption

CAPSULES
B. Soft Capsule

May contain a non-aqueous solution, a

powder or a drug suspension with a
vehicle that is water-miscible (PEG) or
hydrophobic (vegetable oil)

Drugs in hydrophobic vehicle have

poorer absorption than in compressed
tablets

Dosage Form Factors Affecting Absorption

TABLETS

Reduction of effective surface area due to

compression

Excipients:
1.
Anti-frictional agent
-

Aids in compression
Usually hydrophobic, water insoluble reduced
wetting of the surface of the drug particles

2. Granulating agent
-

Makes the powders adhere to each other and form a

larger unit particles or agglomerates (granules)
Too much may produce hard granules

Dosage Form Factors Affecting Absorption

TABLETS
Excipients:
3. Bulking agent
Increases tablet weight to mangeable size
4. Wetting agent, surfactant
Aids in the dissolution of powders
5. Disintegrant
Aids in the breakdown of the tablet into
granules and powders

Dosage Form Factors Affecting Absorption

COATED TABLETS

Coating must breakdown quickly

Sugar coat, film coat

1.
Protect the drug from moisture, light and air
2.
Mask the taste or odor of the drug
3.
Improve the appearance of the tablet
4.
Affect release rate of the drug

Dosage Form Factors Affecting Absorption

MODIFIED RELEASE TABLETS

Have altered rate or timing of drug release

Requires more stringent QC and bioavailability tests

Includes:
-

Extended Release
Delayed Release
e.g. Enteric Coating

Minimizes contact between the drug and the gastric region

(reduced irritation)

Prevent inactivation or degradation of the drug in the stomach

Delay release of the drug until it reaches the small intestine

Dosage Form Factors Affecting Absorption

MODIFIED RELEASE TABLETS
Advantages

Less frequent dosing and better compliance

Reduced variations in plasma level

Disadvantages

More complicated formulation, more erratic result

Dose dumping problem

More expensive technology

Dosage Form Factors Affecting Absorption

TRANSDERMAL DRUG DELIVERY SYSTEMS

Composed of:
Occlusive impermeable backing
Prevents insensible water loss from the skin
Enhances permeation of the skin by the drug
B. Formulation matrix
Maintains the drug concentration within the device
Results to drug partitioning and diffusion into the skin ;
systemic absorption is maintained during the dosing period
C. Adhesive layer
- Ensures drug contact with the skin and continued drug delivery
A.

Dosage Form Factors Affecting Absorption

TRANSDERMAL DRUG DELIVERY SYSTEMS

Dosage Form Factors Affecting Absorption

TARGETED (SITE-SPECIFIC) DRUG DELIVERY SYSTEMS

Systems that place the drug at or near the receptor site by

complexing with a carrier that recognizes the target

Capillary bed of the active site

Special type of cell (tumor cells) but not to normal cells
Specific organ or tissue

Includes

Macromolecular drug carriers (protein-drug carriers)

Particulate drug delivery systems (liposomes, nanoparticles)
Monoclonal antibodies

Dosage Form Factors Affecting Absorption

INSERTS, IMPLANTS AND DEVICES

Drug is impregnated into a

biodegradable or nonbiodegradable material and
inserted in the body

Drug is released slowly for localized

or systemic effect

L-norgestrel implant inserted

beneath the skin of the upper arms
provides contraceptive protection for
5 years

Pathologic Factors Affecting Absorption

Presence of disease such as:
1.
Diarrhea
2.
Constipation
3.
Parkinsons
- decreased GI motility

Pharmacologic Factors Affecting Absorption

Some drugs affect the motility of the GIT

- Decreased GI motility by TCA and antipychotics
- Reduced stomach acid secretion by anticholinergics
Some drugs interfere with the absorption of other drugs