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
Drugs with good aqueous solubility
Drugs formulated as sustained-release
tablets
Noyes-Whitney equation
 What is allowed to pass through
the membrane?
_________________________
_________________________
_________________________
 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. Passive diffusion
B. Active transport
C. Facilitated Diffusion
D. Vesicular transport
E. Convective transport
F. Ion-pair transport
Are you ready?
Mechanisms of Drug Absorption
A. Passive diffusion
B. Active transport
C. Facilitated Diffusion
D. Vesicular transport
E. Convective transport
F. Ion-pair transport
Passive Diffusion
Ficks Law of Diffusion
Active transport
Facilitated diffusion
 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

Weak base
 pH = 1.2 (stomach) pH = 7.4 (blood)
 pH = 1.2 (stomach) pH = 7.4 (blood)

Unonized = 1.0 Ionized = 25,100

Ionized = 0.0158 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 = 25,100

Ionized = 0.0158 Unionized = 1.0____

Total = 1.0158 Total = 25,101

2. The total drug conc. (ionized + non-
ionized) will be unequal on either sides of
the membrane
pH = 1.2 (stomach) pH = 7.4 (blood)

Unionized = 1 Ionized = 25,100

Ionized = 0.0158 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 = 25,100

Ionized = 0.0158 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 A 0.99
C B
-1 90.91 I
9.09 A
- 0.9 88.81 D 11.19 S
I I
- 0.8 86.30 13.70 C
C
- 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)

- 0.4 71.53 28.47

- 0.3 66.61 33.39

A C I D I C
- 0.2 61.32 38.68
- 0.1 55.73 44.27

B A S I C
0 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
 Percent ionized
pka pH If anion (weak acid) If cation (weak base)

+ 0.5 24.03 75.97

+ 0.6 20.07 79.93

A C I D I C
+ 0.7 16.63 83.37
+ 0.8 13.70 86.30

B A S I C
+ 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)
 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