Transcript CHAPTER 6
CHAPTER 7
ABSORPTION KINETICS
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GIT
ABSORPTION
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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 hepato portal system intact into the systemic circulation 5
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 11
Fick ’s law of diffusion
dQ
dt DAk
(
C h
C l
)
x
Q: is the net quantity of drug transferred across the membrane, t: is the time C h : is the conc on one side (GIT) and C l : the other side (plasma) that on 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
pH
pk a
log
C C a s
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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 21
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 C max Cp Absorption Phase Elimination Phase T max 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 k a Absorption Central Compartment (Plasma) k el Elimination
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COMPARTMENTAL MODEL One compartment model with Extravascular administration
Drug in GIT
k a Central Compartment k el 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
dD B dt
Fk a D GI
k el D B dD B dt
Fk a D
0
e
k a t
k el D B
Integrated Equation:
C p
V d
(
Fk a k a D
0
k el
) (
e
k el t
e
k a t
)
C p
A
(
e
k el t
e
k a t
) 28
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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C max and t max
The time needed to reach C max is t max
t
max ln(
k k a a
k k el el
)
At the C max 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 k a and k el In a few cases, the k el obtained from oral absorption data does not agree with that obtained after i.v. bolus injection. For example, the k el calculated after i.v. bolus injection of a drug was 1.72 hr -1 , whereas the k el calculated after oral administration was 0.7 hr -1 . When k a was obtained by the method of residuals, the rather surprising result was that the k a was 1.72 hr -1
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FLIP-FLOP of k a and k el
Drugs observed to have flip-flop characteristics are drugs with fast elimination (k el > k a ) The chance for flip-flop of
ka
and k el 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 k el calculated after oral administration with the k el from intravenous data.
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FLIP-FLOP of k a and k el
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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 k a on C max and T max The faster the absorption the higher is the C max and the shorter is the T max
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Effect of altering k el on C max and T max The faster the elimination the lower is the C max and the shorter is the T max k a = 0.5 hr -1 k el = 0.02 hr -1 k a = 0.5 hr -1 k el = 0.2 hr -1 Cp k a = 0.5 hr -1 k el = 20 hr -1 Time
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Equations
C p
A
(
e
k el t
e
k a t
)
A
V d
(
Fk a k a D
0
k el
)
AUC
F
.
Dose Cl t
max ln(
k a k a
/
k k el el
)
t
1 / 2 0 .
693
k el
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