Transcript CHAPTER 6

CHAPTER 7
ABSORPTION KINETICS
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ABSORPTION
GIT
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ABSORPTION FROM GIT
Oral Dosage Forms
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Advantages of Oral Drugs
 Convenient, portable, no pain
 Easy to take
 Cheap, no need for sterilization
 Compact, multi-dose bottles
 Automated machines producing
tablets in large quantities
 Variety- fast release, enteric coated,
capsules, slow release, …..
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ABSORPTION
Definition: is the net transfer
of drug from the site of
absorption into the circulating
fluids of the body.
For Oral Absorption
1- Cross the epithelium of the
GIT and entering the blood
via capillaries
2- Passing through the hepatoportal system intact into the
systemic circulation
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ABSORPTION
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Biological Membranes
No matter by which route a drug is
administered it must pass through
several to many biological
membranes during the process of
absorption, distribution,
biotransformation and elimination.
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Cell Membrane Structure
It is a bimolecular layer of lipid material entrained
between two parallel monomolecular layers of
proteins.
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Cell Membrane Structure
The cell membrane appears to be perforated by
water-filled pores of various sizes, varying from
about 4 to 10 A
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Drug Transport
Transport is the movement of drug from one place to
another within the body. Most drugs pass through
membranes by diffusion. The process is passive because
no external energy is expended.
PARACELLULAR
TRANSCELLULAR
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PASSIVE DIFFUSION
The passage of drug
molecules occurring from
the side of high drug
concentration to low drug
concentration
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Fick’s law of diffusion
dQ DAk (Ch  Cl )

dt
x
Q: is the net quantity of drug transferred
across the membrane, t: is the time
Ch: is the conc on one side (GIT) and Cl: that on
the other side (plasma)
x: is the thickness of the membrane
A: is surface area of membrane and D: is the
diffusion coefficient related to permeability
k: is the partition coefficient of the drug
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SMALL INTESTINE VILLI
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PERMEABILITY
The permeability of a membrane to a drug depends
on physico-chemical properties of drugs:
Lipophilicity: membranes are highly permeable to lipid
soluble drugs
Molecular size: important in paracellular route and in
drugs bound to plasma protein. Macromolecules such
as proteins do not traverse cell membrane or do so
very poorly
Charge: cell membranes are more permeable to
unionized forms of drugs because of more lipid
solubility
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PERMEABILITY
Cs
pH  pka  log
Ca
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Carrier-Mediated Transport
Active Transport
The drug is transported against a concentration gradient .This
system is an ENERGY consuming system.
Example: Glucose and Amino acids transport.
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Passive Facilitated Diffusion
A drug carrier is
Required but no ENERGY
is necessary. e.g. vitamin
B12 transport. Drug
moves along conc
gradient (from high to
low), downhill but faster
DRUG
CARRIER
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DRUG TRANSPORT
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Characteristics of GIT
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Effect of Food on Drug Absorption
Propranolol
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Effect of Diseases on Drug Absorption
Diseases that cause changes in:
 Intestinal blood flow
 GI motility
 Stomach emptying time
 Gastric and intestinal pH
 Permeability of the gut wall
 Bile and digestive enzyme secretion
 Alteration of normal GI flora
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Simulation of Drug Absorption by
Dissolution Methods
Dissolution tests in vitro measure the rate and
extent of dissolution of the drug from a dosage
form in an aqueous medium
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ABSORPTION KINETICS
Plasma Concentration-Time Curve
Cmax
Cp
Absorption
Elimination
Phase
Phase
Tmax
Time
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First-Order Absorption
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Absorption
Zero-Order Absorption: is seen with controlled
release dosage forms as well as with poorly soluble
drugs. The rate of input is constant.
First-Order Absorption: is seen with the majority of
extravascular administration (oral, IM, SC, rectal,
ect..) Most PK models assume first-order absorption
unless otherwise stated.
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One Compartment Model for First-Order
Absorption and First-Order Elimination
Gastrointestinal, Percutaneous, Subcutaneous,
Intramuscular, Ocular, Nasal, Pulmonary, Sublingual,…
Drug in dosage
form
Release
Drug particles
In body fluid
Dissolution
Drug in
solution
Central
Compartment
Absorption
(Plasma)
ka
kel
Elimination
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COMPARTMENTAL MODEL
One compartment model with Extravascular
administration
Drug in
GIT
ka
Central
Compartment
kel
Route of Administration: Oral, IM, SC, Rectal, ect…
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First-Order Absorption Model
Rate of change = rate of input – rate of output
dDB
 Fk a DGI  kel DB
dt
dDB
 Fk a D0 e  kat  kel DB
dt
Integrated Equation:
Fka D0
 kel t
kat
Cp 
(e
e )
Vd (ka  kel )
Cp  A(e
 kel t
e
 ka t
)
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The Residual Method
The rising phase is not log-linear because absorption
and elimination are occurring simultaneously
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The Residual Method
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The Residual Method
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The Residual Method
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Cmax and tmax
The time needed to reach Cmax is tmax
ln(k a  kel )
t max 
k a  kel
At the Cmax the rate of drug absorbed is
equal to the rate of drug eliminated
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Lag Time
The time delay prior to the commencement of
first-order drug absorption is known as lag time
Cp
Lag time
Time
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FLIP-FLOP of ka and kel
In a few cases, the kel obtained from oral
absorption data does not agree with that
obtained after i.v. bolus injection. For
example, the kel calculated after i.v. bolus
injection of a drug was 1.72 hr -1, whereas
the kel calculated after oral administration
was 0.7 hr -1. When ka was obtained by the
method of residuals, the rather surprising
result was that the ka was 1.72 hr -1
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FLIP-FLOP of ka and kel
Drugs observed to have flip-flop
characteristics are drugs with fast elimination
(kel > ka)
The chance for flip-flop of ka and kel is
greater for drugs that have a kel > 0.69 hr-1
The flip-flop problem also often arises when
evaluating controlled-release products
The only way to be certain of the estimates
is to compare the kel calculated after oral
administration with the kel from intravenous
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data.
FLIP-FLOP of ka and kel
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Effect of size of the dose of a drug on the peak
concentration and time of peak concentration
The time of peak conc is the same for all doses
A >B >C
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Effect of altering ka on Cmax and Tmax
The faster the absorption the higher is the Cmax and the
shorter is the Tmax
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Effect of altering kel on Cmax and Tmax
The faster the elimination the lower is the Cmax and the
shorter is the Tmax
ka= 0.5 hr-1
kel= 0.02 hr-1
ka= 0.5 hr-1
kel= 0.2 hr-1
Cp
ka= 0.5 hr-1
kel= 20 hr-1
Time
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Equations
C p  A (e
Fka D0
A
Vd (k a  k el )
F .Dose
AUC 
Cl
 kel t
e
 ka t
tmax
)
ln(ka / kel )

ka  kel
t1 / 2
0.693

k el
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