chapter 7

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CHAPTER 7

ABSORPTION KINETICS

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ABSORPTIONGIT

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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 Absorption1- 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.

TRANSCELLULARPARACELLULAR

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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

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

x

CCDAk

dt

dQ lh )(

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SMALL INTESTINE VILLI

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PERMEABILITYThe 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

a

sa C

CpkpH log

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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

CARRIER

DRUG

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DRUG TRANSPORT

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Characteristics of GIT

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Effect of Food on Drug AbsorptionPropranolol

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Effect of Diseases on Drug AbsorptionDiseases 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 MethodsDissolution 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 KINETICSPlasma Concentration-Time Curve

Absorption

Phase

Elimination

Phase

Time

Cp

Cmax

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

Drug particlesIn body fluid

Drug in solution

CentralCompartment

(Plasma)

Release

Dissolution

ka kel

EliminationAbsorption

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COMPARTMENTAL MODEL

One compartment model with Extravascular

administration

Route of Administration: Oral, IM, SC, Rectal, ect…

CentralCompartment

ka kelDrug inGIT

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First-Order Absorption ModelRate of change = rate of input – rate of output

Integrated Equation:

BelGIaB DkDFk

dt

dD

Beltk

aB DkeDFk

dt

dDa

0

)()(

0 tktk

elad

ap

ael eekkV

DFkC

)( tktkp

ael eeAC

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The Residual MethodThe 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

ela

ela

kk

kkt

)ln(

max

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Lag TimeThe time delay prior to the commencement of

first-order drug absorption is known as lag time

Time

Cp

Lag 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 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 concentrationThe time of peak conc is the same for all doses

A >B >C

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Effect of altering ka on Cmax and TmaxThe faster the absorption the higher is the Cmax and the

shorter is the Tmax

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The faster the elimination the lower is the Cmax and the

shorter is the Tmax

Effect of altering kel on Cmax and Tmax

Cp

ka= 0.5 hr-1

kel= 0.2 hr-1

ka= 0.5 hr-1

kel= 20 hr-1

Time

ka= 0.5 hr-1

kel= 0.02 hr-1

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Equations

)( tktkp

ael eeAC

)(0

elad

a

kkV

DFkA

ela

ela

kk

kkt

)/ln(max

elkt

693.02/1

Cl

DoseFAUC

.