Mechanisms of Drug

Absorption

LADMERT

Definition of terms

Absorption
Adsorption
Drug product
Bioavailability
Drug delivery system

Drug Product
Finished dosage form or formulation that
contains the active drug ingredient in
association with nondrug (usually inactive)
ingredients (excipients) that make up the
vehicle, or formulation matrix

Bioavailability
Measurement of the rate and extent
(amount) of active drug that reaches the
systemic circulation

Drug Delivery System

More comprehensive concept that
includes the drug formulation and the
dynamic interactions among the drug, its
formulation matrix, its container and the
patient

Systemic absorption of drug

depends on.
Nature of the drug product
Physicochemical properties of the drug
Anatomy and physiologic functions at the
site of absorption

What happens when you

ingest a tablet?

Systemic absorption of drug

products consists of a succession
of rate processes

Rate processes
Disintegration of the drug product and
subsequent release of the drug
Dissolution of a drug in aqueous
environment
Absorption across membranes into the
systemic circulation

 The rate at which a drug reaches the

systemic circulation can be determined by
the slowest step of the sequence of kinetic
process (rate-limiting step)

What is the rate-limiting step?

Drugs with poor aqueous solubility rate
of dissolution
Drugs with good aqueous solubility rate
of absorption
Drugs formulated as sustained-release
tablets rate of disintegration

What is allowed to pass through the

membrane?
Lipid soluble
unionized
Small molecular size

Theories
Davson & Danielli lipid bilayer or unit
theory
explains why lipid-soluble drugs tend to
penetrate more easily than polar drugs

 Does not account for the diffusion of

water, small-MW molecules such as urea,
and certain charged ions

Theories
Singer & Nicolson fluid mosaic model
explains the transcellular diffusion of polar
molecules
two types of pores: 10 nm & 50-70 nm
small pores: water, ions (Na, K, Cl) &
urea

Mechanisms of Drug Absorption

A.
B.
C.
D.
E.
F.

Passive diffusion
Active transport
Facilitated Diffusion
Vesicular transport
Convective transport
Ion-pair transport

Are you ready?

Mechanisms of Drug Absorption

A.
B.
C.
D.
E.
F.

Passive diffusion
Active transport
Facilitated Diffusion
Vesicular transport
Convective transport
Ion-pair transport

Passive Diffusion
Area of high conc. to an area of low conc.
No expenditure of energy
Moves along a conc. gradient

Ficks Law of Diffusion

Rate of absorption = DAk (Ci Co)/h
D = diffusion rate constant
A = surface area of the absorbing surface
k = lipid/water partition coefficient
(Ci Co) = concentration difference on each
side of the membrane
h = thickness of the membrane

Active transport

Area of low conc. to an area of high conc.

With expenditure of energy
Moves against a conc. Gradient
Carrier-mediated hence it can be
saturated

Facilitated diffusion
Move from an area of high conc. to an
area of low conc.
No expenditure of energy
Moves along a conc. Gradient
carrier-mediated hence it can be saturated

Vesicular transport
Endocytosis
Exocytosis
Transcytosis

Convective transport

Ion-pair transport
Propranolol oleic acid
Quinine hexylsalicylate
Amphotericin B DSPG
(disteroylphosphatidylglycerol)

Transport proteins
ATP-binding cassette (ABC)
Solute carrier (SLC)
Influx transport proteins (PepT1)
Efflux transport proteins (P-gp)

Transport protein
P-glycoprotein (mdr protein)
Efflux of nifedipine, digoxin, cyclosporin

P-glycoprotein

Absorption of Partially-ionized
drugs
Aspirin pka = 3
Paracetamol pka = 9.5
Ibuprofen pka = 4.4

 For acidic drugs, the lower the pka the

stronger the acid
For basic drugs the higher the pka the
stronger the base

Henderson-Hasselbalch
equation
Weak acid
pH = pka + log ionized/unionized
Weak base
pH = pka + log unionized/ionized

 pH = 1.2 (stomach)

pH = 7.4 (blood)

 pH = 1.2 (stomach)

pH = 7.4 (blood)

Unonized = 1.0
Ionized = 0.0158

Ionized = 25,100
Unionized = 1____

Total = 1.0158

Total = 25,101

pH-partition hypotheses

If the pH on one side of a cell

membrane differs from the pH on the
other side of the membrane, then:

pH = 1.2 (stomach)

pH = 7.4 (blood)

1. The drug will ionize to different

degrees on respective sides of the
membrane
pH = 1.2 (stomach)

pH = 7.4 (blood)

Unonized = 1.0
Ionized = 0.0158

Ionized = 25,100
Unionized = 1.0____

Total = 1.0158

Total = 25,101

2. The total drug conc. (ionized + nonionized) will be unequal on either sides
of the membrane
pH = 1.2 (stomach)

pH = 7.4 (blood)

Unionized = 1
Ionized = 0.0158

Ionized = 25,100
Unionized = 1____

Total = 1.0158

Total = 25,101

3. The compartment in which the drug is

more highly ionized will contain the
greater total drug conc.
pH = 1.2 (stomach)

pH = 7.4 (blood)

Unionized = 1.0
Ionized = 0.0158

Ionized = 25,100
Unionized = 1.0____

Total = 1.0158

Total =

25,101

Percent ionized
pka - pH

If anion (weak acid)

If cation (weak base)

-4

99.99 (3-7)

0.01 (9-13)

-3

99.94

0.06

-2

99.01

0.99

-1

90.91

9.09

- 0.9

88.81

11.19

- 0.8

86.30

13.70

- 0.7

83.37

16.63

- 0.6

79.93

20.07

- 0.5

75.97

24.03

Percent ionized
pka - pH

If anion (weak acid)

If cation (weak base)

-4

99.99 (3-7)

0.01 (9-13)

-3

99.94

0.06

-2

99.01

-1

90.91

- 0.9

88.81

- 0.8

86.30

13.70

- 0.7

83.37

16.63

- 0.6

79.93

20.07

- 0.5

75.97

24.03

A
CI
DI
C

0.99
9.09
11.19

B
A
SI
C

Percent ionized
If anion (weak acid)

If cation (weak base)

71.53

28.47

- 0.3

66.61

33.39

- 0.2

61.32

- 0.1

55.73

50.0

50.0

+ 0.1

44.27 (3-2.9)

55.73 (9-8.9)

+ 0.2

38.68

61.32

+ 0.3

33.39

66.32

+ 0.4

28.47

66.61

ACIDIC

- 0.4

38.68
44.27

BASIC

pka - pH

Percent ionized
pka pH

If anion (weak acid)

If cation (weak base)

24.03

75.97

+ 0.6

20.07

79.93

+ 0.7

16.63

+ 0.8

13.70

+ 0.9

11.19

88.81

+1

9.09

90.91

+2

0.99

99.01

+3

0.06

99.94

+4

0.01 (5-1)

99.99 (9-5)

83.37
86.30

BASIC

ACIDIC

+ 0.5

 The relation between ionization and pH is

sigmoidal

Just Remember
An acidic drug in an acidic medium is
predominantly UNIONIZED
An acidic drug in a basic medium is
predominantly IONIZED

Just Remember
A basic drug in a basic medium is
predominantly UNIONIZED
A basic drug in an acidic medium is
predominantly IONIZED

What is the % ionization of a drug with a pka

of 8.5 found in a medium with a pH of 2?

Clinical Application
Sodium bicarbonate IV is given as a
treatment of aspirin toxicity.

The movement of drugs across

biologic membranes is influenced by:
1. Mechanism of transport (e.g. passive
diffusion, active transport, cotransport,
antiport)
2. Binding affinity for tissue or plasma
proteins
3. Degree of ionization (for weak acid,
weak bases) influenced by the pka of the
drug & pH of the medium

Lipid/water partition coefficient

Ratio of the concentration of a drug in two
immiscible or slightly miscible phases

Apparent lipid/water partition

coefficient
Lipid phase (octanol, chloroform,
cyclohexane, isopropyl myristate)
Aqueous phase (buffer solution of a
particular pH)
Specified temperature (37 degrees
Celsius)

Apparent partition coefficient

Equilibration is done for a minimum of 3
hours

Apparent lipid/water partition

coefficient
APC = (Co2 C2) x a / (C2 x b)
APC = apparent lipid/water partition coefficient
Co2 = drug concentration in aqueous phase
before equilibration
C2 = drug concentration in aqueous phase after
equilibration
a = volume of lipid phase
b = volume of aqueous phase

 Measure of the relative affinity of a drug

for two immiscible solvents
Index of comparative solubilities of
solvents
Parameter of the relative rate of
partitioning from one phase to another

 In vivo partitioning does not occur

between two immiscible liquids but does
occur between physiological fluids
separated by membranes
In vitro guide in the absorption of
drugs in the stomach, buccal cavity,
colon & skin