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7/29/2019 - Drug Absorption - Fev 2010
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Drug Absorption
PHCL 2XX
Dr VN NDIKUM
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Pharmacokinetic Overview (PK)
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Pharmacokinetic Overview .
12
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Pharmacokinetic Overview .
Definition of PK: The study of the movement of drugs in the body, including
the processes of absorption, distribution, localization intissues, biotransformation and excretion. The actions of thebody on the drug are called pharmacokinetic processes
Pharmacokinetic processes govern the absorption,distribution, metabolism and elimination of drugs
Learning pharmacokinetics is of great practicalimportance in the choice and administration of a
particular drug for a particular patient, e.g., onewith impaired cardiac, hepatic or renal function
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Drug Absorption
Absorption is the process by which a drug entersthe bloodstream without being chemically altered,
Or
The movement of a drug from its site ofapplication into the blood or lymphatic system.
NB:
Absorption is instantaneous for bolus intravenousadministration. Drugs taken by mouth pass to the stomach & then
the intestine they are absorbed from the GItractinto the circulatory system
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Most drugs cross biomembranes by passive diffusion where the
rate of absorption is proportional to the drug concentration
gradient. In which case will the rate be larger?
Out In
A B
Out In
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The Movement of Drug MoleculesAcross Cell Barriers
Cell membranes form the barriers betweenaqueous compartments in the body.
The most universal function of cellmembrane is to act as a selective barrier to
the passage of molecules, allowing somemolecules to cross while excluding others. The cell membrane consists of a bimolecular
lipid sheet (hydrophobic) interspersed withprotein molecules (hydrophilic), and contains
minute aqueous pores which allow passageof small hydrophilic substances.
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The Movement of Drug MoleculesAcross Cell Barriers
Cell membranes form the barriersbetween aqueous compartments inthe body.
The most universal function of cellmembrane is to act as a selective
barrier to the passage of molecules,allowing some molecules to crosswhile excluding others.
The cell membrane consists of abimolecular lipid sheet
(hydrophobic) interspersed withprotein molecules (hydrophilic), andcontains minute aqueous poreswhich allow passage of smallhydrophilic substances
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Factors which influence the rate ofabsorption
1. Mechanism of transportation acrossmembrane
2. the physicochemical properties of the
drug3. routes of administration
4. dosage forms
5. circulation at the site of absorption6. concentration of the drug
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Mechanisms of solute transport acrossmembranes
passive diffusion
filtration and bulk flow
endocytosis
active transport
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Mechanism of transport-Passive diffusion
Passive diffusion is the direct movement of asolute through a biologic barrier from the phasesof higher concentration to a phase of lowerconcentration.
This is the most common mechanism oftransport.
The rate of diffusion is related to lipid solubility
and polarity, pH, etc. The concentration gradient is the most important
factor in determining rate.
Example include phenobarbital
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Mechanism of transport- Filtration
Involves the bulk flow of water related toosmotic and hydrostatic pressures.
Small water soluble, polar and non-polar,substances are transported by this process.
It is most probable that these substance passthrough spaces between cells rather than acrossthe cell membrane.
It is a purely physical process and the mostimportant force is a pressure gradient.
Examples include water and urea.
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Passive diffusion
Aqueous diffusion
Drug passes through
aqueous pores in
biomembranes BUT
these pores limited to
molecular wts of
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Mechanism of transport - SpecializedTransport Mechanisms
1. Facilitated diffusion or transport: This is a carrier mediated transport system
It is characterized by: Selectivity, Competitiveness,Saturability, Concentration gradient
2. Active transport is a carrier mediated transport system,
energy is required and the transport is against a concentrationgradient.
is characterized by saturability, selectivity, andcompetitiveness.
3. Pinocytosis requires energy.
The transport mechanism is by invagination of the cellmembrane to form a vesicle and the engulfing of theinvagination
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Mechanism Direction Energyrequired
Carrier Saturable
Passive
diffusion
Along gradient No No No
Facilitateddiffusion
Along gradient No Yes Yes
Active transport Againstgradient
Yes Yes Yes
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Drug Absorption:Factors which influence the rate of absorption
1. types of transport
2. the physicochemical propertiesof the drug
3. routes of administration
4. dosage forms
5. circulation at the site of absorption
6. concentration of the drug
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physicochemical factors of a drug thatcould influence transport
Following drug administration, thererelease of active drug from dosage form
Disintegration and dissolution as critical
steps in oral absorption Characteristics of the drug (solute) and the
physicochemical factors influencing transport:
Molecular size and shape
Lipid solubility
Partition coefficient - relation to lipid solubility
Weak acids - weak bases
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Lipid-Water Partition Coefficient (P.C
The ratio of the concentration of
the drug in two immiscible phases: Phase 1: a nonpolar liquid or organic
solvent (representing the membrane);
and Phase 2: an aqueous buffer, pH 7.4
(representing the plasma)
The higher the lipid/water p.c. the
greater the rate of transfer acrossthe membrane
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Drug Absorption:Factors which influence the rate of absorption
1. types of transport
2. the physicochemical properties of thedrug
3. routes of administration
4. dosage forms
5. circulation at the site of absorption
6. concentration of the drug
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Routes of Drug Administration
The route of administration (ROA) that ischosen may have a profound effect upon thespeed and efficiency with which the drug acts(see lecture on routes of administration)
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Drug Absorption:Factors which influence the rate of absorption
1. types of transport
2. the physicochemical properties of the
drug3. routes of administration
4. dosage forms
5. circulation at the site of absorption6. concentration of the drug
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Factors which influence the rate of absorption:concentration of the drug
The concentration of a drug at the site ofabsorption could influence the rate of absorption
The higher the concentration, the higher the rateof absorption
Example: Time-release preparations
Oral - controlled-release, timed-release, sustained-release designed to produce slow,uniform absorption for 8 hours
or longer
better compliance, maintain effect over night, eliminateextreme peaks and troughs
Depot or reservoir preparations parental administration (except IV), may be prolonged by
using insoluble salts or suspensions in non-aqueous vehicles.
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Drug Absorption:Factors which influence the rate of absorption
1. types of transport
2. the physicochemical properties of the
drug3. routes of administration
4. dosage forms
5. circulation at the site of absorption6. concentration of the drug
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Factors which influence the rate of absorption:Dosage Form -
Form of preparation of administereddrug could also determine the rate ofabsorption.
The rate of absorption will depend onthe solubility and ease of dissolutionof the drug
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Drug Absorption:Factors which influence the rate of absorption
1. types of transport
2. the physicochemical properties of the
drug3. routes of administration
4. dosage forms
5. circulation at the site of absorption6. concentration of the drug
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Factors which influence the rate of absorption:Blood circulation at various organs
The rate of absorption will also depend onthe rate of blood flow in the organ wherethe drug is absorbed.
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Factors which influence the rate of absorption:Blood circulation at various organs
Tissue Mass (kg) Blood Flow(mL/min)
Flow (percentof Cardiac
Output)
Brain 1.4 750 13.9
Heart 0.3 250 4.9
Liver 2.9 1500 27.8
Kidneys 0.3 1260 23.3
Skeletal muscle 34.4 840 15.6
Skin 4.0 462 8.6
Placenta andfetal
(term)3.8 500 9
Whole body 70 5400 100
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In summary
TheRate of Absorptionis determinedby the physical characteristics of thedrug, the speed which the drug is
absorbed and/ or released, as wellas the need to bypass hepaticmetabolism and achieve high conc. at
particular sites
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Absorption of Oral drugs
Dose
Destroyed
in gut
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
to
systemic
circulation
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Absorption
of inhaledproducts
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Absorption from the Skin
Must cross several cell layers (stratumcorneum, epidermis, dermis) to reachblood vessels.
Factors important here are:lipid solubility
hydration of skin
site (e.g. sole of feet vs. scrotum)
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Other Routes of Exposure
Intraperitoneal large surface area, vascularized, first pass
effect.
Intramuscular, subcutaneous, intradermal: absorption through endothelial pores into the
circulation; blood flow is most important +other factors
Intravenous
Ph ki i P h
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Pharmacokinetic Parameters that areused to describe absorption
1. Bioavailability ( la biodisponibilit) F Describes Measures Rate and Extent of Drug
Absorption into the Systemic Circulation
2. Tmax
3. Cmax
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Bioavailability (F):
Bioavailability (F): the fraction of the dose that reaches the
systemic circulation. (F=1 for IVadministration.)
Absolute Bioavailability: Estimation of F for any other route in
comparison to intravenous administration.
Relative Bioavailability: Estimation of F for a dosage form to another
given by anextravascular (non-intravenous)route of administration.
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Determinants ofBIOAVAILABIITY
Affected by: 1st pass metabolism
(eg: Lidocaine,propranolol)
Solubility Instability
(eg: Penicillin G, insulin)
Seru
mC
oncen
tration
Time
Injected Dose
Oral Dose
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Area under the Curve (AUC)
AUC is a quantitative measurement ofBioavailability
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Bioavailability
The fraction of the dose of a drug (F) thatenters the general circulatory system,
F= amt. Of drug that enters systemic circul.
Dose administered
F = AUC/Dose
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Examples: If the drugs bioavailability is 50%, the body
will only absorb 250 mg of a 500 mg dose.
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Time to Peak Concentration (Tmax)
0
10
20
3040
50
60
70
80
90
100
0 min 5 min 10 min 20 min 30 min 60 min 120
min
180
min
IV
Oral
Rectal
Question: Which route has the lowest Tmax?
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Maximum Concentration (Cmax)
0
10
20
3040
50
60
70
80
90
100
0 min 5 min 10 min 20 min 30 min 60 min 120
min
180
min
IV
Oral
Rectal
Question: Which route has the Highest Cmax?
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Plasma levelcurve
Cmax= maximal druglevel obtained with thedose.
Tmax = time at whichCmax occurs.
Lag time = time fromadministration to
appearance in blood. Onset of activity = time
from administration toblood level reachingminimal effective
concentration (MEC). Duration of action = time
plasma concentrationremains greater than MEC.
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