ABSORPTION KINETICS

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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 hepato-portal 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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Ficks law of diffusion

• 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
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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

Tmax
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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
Central Compartment (Plasma)
ka
kel
Drug in solution
Elimination
Absorption
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COMPARTMENTAL MODEL

• One compartment model with Extravascular
• administration

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
• Integrated Equation

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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

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 gt ka)
• The chance for flip-flop of ka and kel is greater
  for drugs that have a kel gt 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 data.

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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 gtB gtC
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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

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Equations