ToxicokineticsToxicokinetics

ToxicokineticsToxicokinetics is the study of the drug movement is the study of the drug movement around the body (Absorption, Distribution, around the body (Absorption, Distribution, metabolism, and Elimination)metabolism, and Elimination)

ToxicokineticToxicokinetic data is best derived using radio labeled data is best derived using radio labeled dose of the drug. dose of the drug. This allows for following the fate of This allows for following the fate of the drugthe drug, metabolic products, distribution in the , metabolic products, distribution in the tissue, storage sites, as well as its elimination. tissue, storage sites, as well as its elimination. Unfortunately, these methods do not provide Unfortunately, these methods do not provide knowledge about proportion of the drug left intact to knowledge about proportion of the drug left intact to its metabolites.its metabolites.

TK is concerned with what the body does to the TK is concerned with what the body does to the toxicant.toxicant.

TOXICOKINETICSTOXICOKINETICS

Toxicokinetics

Absorption

Distribution

Metabolism

Excretion

Ingestion

Inhalation

Skin penetration

Parenteral

Phase 1

Phase 2

Kidney

Lung

Feces

Saliva

Lactation

Sweating

Circulation

Adipose tissue

Highly perfused ogan

Quantitative modelCompartment

Parameters

Clearance

Half-life

Volume of distribution

Bioavailability

Membrane transportationActive

Passive

Physiological-based TK

Non-compartment

Order of reactionZero

First

Blood-brain barrier

ToxicodynamicsToxicodynamics

ToxicodynamicsToxicodynamics is the study of toxic actions is the study of toxic actions

of of xenobioticxenobiotic substances on living systems.substances on living systems.

ToxicodynamicsToxicodynamics is concerned with processes is concerned with processes

and changes that occur to the drug at the target and changes that occur to the drug at the target

tissue, including metabolism and binding that tissue, including metabolism and binding that

results in an adverse effect.results in an adverse effect.

Simply, TD is concerned with what the Simply, TD is concerned with what the

toxicant do to the bodytoxicant do to the body

DosageExposure

ToxicEffects

PlasmaConc.

Site ofaction

Toxicokinetics Toxicodynamics

ToxicokineticToxicokinetic (TK) processes(TK) processes

xenobiotic

ABSORPTION DISTRIBUTION METABOLISM EXCRETION

EXTERNAL

MEMBRANE

BARRIERS

skin

G.I. tract

lungs depots

BLOOD PLASMA

TISSUES

PHASE-1

PHASE-2

KIDNEYS

LIVER

lungs

saliva

sweat

breast milk

Disposition of Disposition of XenobioticsXenobiotics

absorption

excretion

Blood and lymph

Liver

Intravenous Intraperitoneal

Subcutaneous

Intramuscular

Dermal

extracellular

fluidfat

Secretory

Structures

Bile

Kidney Lung

Bladder Alveoli

Urine Expired Air Secretions

body

organs

softtissue bone

Gastrointestinal

tractLung

feces

InhalationIngestion

distribution

ToxicokineticsToxicokinetics (ADME)(ADME)

ToxicokineticsToxicokinetics study four processes:study four processes:

1.1. AbsorptionAbsorption

2.2. DistributionDistribution

3.3. MetabolismMetabolism

4.4. ExcretionExcretion

Metabolism and excretion processes are Metabolism and excretion processes are

combined as a single process called combined as a single process called

eliminationelimination

The The toxicokineticstoxicokinetics of a chemical are determined of a chemical are determined

by measuring the concentrations of the by measuring the concentrations of the

chemical in plasma (usually) or blood at chemical in plasma (usually) or blood at

various times following a single dose. The various times following a single dose. The

fundamental parameters that define the rates fundamental parameters that define the rates

and extents of distribution and elimination are and extents of distribution and elimination are

derived from data following an intravenous or derived from data following an intravenous or

oral dose. oral dose.

Important principles of Important principles of

toxicokineticstoxicokinetics

The effect which a drug produces is The effect which a drug produces is

dependent on:dependent on:

1.1. The doseThe dose

2.2. The concentration in the target organThe concentration in the target organ

The kinetics of a drug may differ from The kinetics of a drug may differ from

therapeutic dose to its toxic dosetherapeutic dose to its toxic dose

ToxicokineticsToxicokinetics is important in predicting the is important in predicting the

plasma concentration of a drugplasma concentration of a drug

ToxicokineticsToxicokinetics and toxicityand toxicity

Toxicity depends on:Toxicity depends on:

Duration and concentration of drugDuration and concentration of drug at the portal of entryat the portal of entry

The rate and amount (extent) of drug absorbedThe rate and amount (extent) of drug absorbed; toxicity ; toxicity will be low at slow absorption rates. This means that a highly will be low at slow absorption rates. This means that a highly toxic drug that is poorly absorbed may have same hazard as toxic drug that is poorly absorbed may have same hazard as another with low toxicity but is highly absorbed.another with low toxicity but is highly absorbed.

The distribution of drug within the bodyThe distribution of drug within the body; where most drugs ; where most drugs are distributed in highly are distributed in highly perfusedperfused organs like brain, liver and organs like brain, liver and kidneys. However, in some cases, the organ in which the drug kidneys. However, in some cases, the organ in which the drug is concentrated may not necessarily suffer the damage. An is concentrated may not necessarily suffer the damage. An example is example is organochlorineorganochlorine compounds concentrated in adipose compounds concentrated in adipose tissue while the target organ is the brain.tissue while the target organ is the brain.

The efficiency of biotransformation and nature of The efficiency of biotransformation and nature of metabolitesmetabolites; where, in some cases, a drug may be ; where, in some cases, a drug may be transformed to a more toxic metabolite or a more transformed to a more toxic metabolite or a more lipid soluble or water soluble metabolite, which lipid soluble or water soluble metabolite, which affects absorption and distributionaffects absorption and distribution

The ability of the drug to pass through cell The ability of the drug to pass through cell membranes and interact with cell constituentsmembranes and interact with cell constituents. . Example, some Example, some organochlorinesorganochlorines affect the DNAaffect the DNA

The amount and storage duration of the drug or The amount and storage duration of the drug or its metabolites in the tissueits metabolites in the tissue. These may induce . These may induce toxicity after a long time after exposure. Lead in toxicity after a long time after exposure. Lead in bones is an examplebones is an example

The rate and site of excretionThe rate and site of excretion; where the more rapid ; where the more rapid the excretion, the less toxicity it will produce the excretion, the less toxicity it will produce

1. Absorption1. AbsorptionThe term absorption describes the process of the transfer of theThe term absorption describes the process of the transfer of theparent chemical from the site of administration into the generalparent chemical from the site of administration into the generalcirculation, and applies whenever the chemical is administered circulation, and applies whenever the chemical is administered via via an an extravascularextravascular route (route (i.e. i.e. not by direct intravascular not by direct intravascular injection).injection).

Many chemicals will be metabolized or transformed during Many chemicals will be metabolized or transformed during their passage from the site of administration into the their passage from the site of administration into the general circulation, so that little parent chemical may general circulation, so that little parent chemical may reach the general circulationreach the general circulation, this raises the possibility of , this raises the possibility of confusion in discussing the confusion in discussing the extent of absorptionextent of absorption depending on depending on whether the data refer to the parent chemical, or to metaboliteswhether the data refer to the parent chemical, or to metabolitesor both (when or both (when radiolabelingradiolabeling is used). This confusion is is used). This confusion is resolved by the proper use of the term resolved by the proper use of the term bioavailabilitybioavailability (the (the fraction of the dose administered that reaches the general fraction of the dose administered that reaches the general circulation as the parent compound) to describe the extent of circulation as the parent compound) to describe the extent of absorption.absorption.

Mechanism of Membrane Permeation

1. Passive diffusion

2. Active transport

3. Facilitated transport

4. Pinocytosis and phagocytosis

Drugs are absorbed by the following Drugs are absorbed by the following

processes:processes:

1.1. Passive transportPassive transport

This can occur by simple diffusion due to concentration This can occur by simple diffusion due to concentration gradient orgradient or

By passage of drugs through the pores (of the kidney and By passage of drugs through the pores (of the kidney and capillaries), i.e. by filtrationcapillaries), i.e. by filtration

Passive transport is affected by:Passive transport is affected by:

Ability of the drug to dissolve in the lipid portion of the cellAbility of the drug to dissolve in the lipid portion of the cellmembranemembrane

The size of the drug, in case it is water soluble. Aqueous The size of the drug, in case it is water soluble. Aqueous pores are about 4Apores are about 4Aoo which will allow drugs of 100which will allow drugs of 100--200 200 amuamuto passto pass

Presence of the drug in its Presence of the drug in its nonionizednonionized formform

Uptake by Passive diffusionUptake by Passive diffusion

Uncharged molecules may diffuse along

conc. gradient until equilibrium is

reached

No substrate specificity

Small MW < 0.4 nm (e.g. CO, N20,

HCN) can move through cell pores

Lipophilic chemicals may diffuse

through the lipid bilayer

Uptake by Passive diffusionUptake by Passive diffusion

First order rate diffusion, depends on

Concentration gradient

Surface area (alveoli 25 x body surface)

Thickness

Lipid solubility & ionization

Molecular size (membrane pore size = 4-40 A,

allowing MW of 100-70,000 to pass through)

FlicksFlicksss law and Diffusion law and Diffusion

Where;

dD/dt = rate of mass transfer across the membraneK = constant (coefficient of permeability)A = Cross sectional area of membrane exposed to the

compound

C0 = Concentration of the toxicant outside the membrane

Ci = Concentration of the toxicant inside the membrane

t = Thickness of the membrane

dD/dt = KA (Co - Ci) / t

2. 2. Special transportSpecial transport

Two types of special transport mechanisms can Two types of special transport mechanisms can

be identified:be identified:

1.1. Active diffusionActive diffusion: :

Independent of or against conc. gradient

Require energy

Substrate specific

Rate limited by no. of carriers

Example: Ca-pump (Ca2+ -ATPase)

2. Facilitated diffusion2. Facilitated diffusion: Occurs when a drug has : Occurs when a drug has a specific carrier protein, and does not occur a specific carrier protein, and does not occur against concentration gradientagainst concentration gradient

Carried by trans-membrane carrier along concentration gradient

Energy independent

May enhance transport up to 50,000 folds

Example: Calmodulin for facilitated transport of Ca2+

3. Additional transport3. Additional transport: occurs by : occurs by endocytosisendocytosis; ;

where :where :

Phagocytes (cell eating) engulf the solid large Phagocytes (cell eating) engulf the solid large

particles suspended in the intracellular fluidparticles suspended in the intracellular fluid

PinocytesPinocytes (cell drinking) in which very small (cell drinking) in which very small

suspended particles or liquids are engulfedsuspended particles or liquids are engulfed

Factors affecting gastrointestinal Factors affecting gastrointestinal

absorptionabsorption

1. Types of cells at the specific site: 1. Types of cells at the specific site:

An example is the sublingual cells which are highly An example is the sublingual cells which are highly vascularizedvascularized which allows for rapid absorptionwhich allows for rapid absorption

2. Period of time that drugs remain at the site:2. Period of time that drugs remain at the site:

Drugs are poorly absorbed within the mouth because the Drugs are poorly absorbed within the mouth because the time a drug spends in the mouth is very short, while time a drug spends in the mouth is very short, while high absorption can occur in the intestine due to the high absorption can occur in the intestine due to the long time a drug spends therelong time a drug spends there

3. pH 3. pH

This factor affects the This factor affects the ionizabilityionizability of the drug. of the drug.

The acidic nature of the fluid in the stomach The acidic nature of the fluid in the stomach

facilitates the absorption of weakly acidic facilitates the absorption of weakly acidic

drugs, while both weakly acidic and basic drugs, while both weakly acidic and basic

drugs are well absorbed in the small intestine drugs are well absorbed in the small intestine

since the pH there is almost neutralsince the pH there is almost neutral

4. The concentration at the absorption site4. The concentration at the absorption site

5. Presence of food or binding substances:5. Presence of food or binding substances:

These will decrease the concentration of the free These will decrease the concentration of the free

drug and thus will lower its absorptiondrug and thus will lower its absorption

6. Rate of gastric emptying:6. Rate of gastric emptying:

As emptying rate is decreased, absorption in the As emptying rate is decreased, absorption in the stomach will increasestomach will increase

7. Gastrointestinal motility:7. Gastrointestinal motility:

This will decrease the amount absorbed in the stomach This will decrease the amount absorbed in the stomach while increase the amount absorbed in the intestinewhile increase the amount absorbed in the intestine

8. Absorbing surface area of the intestine8. Absorbing surface area of the intestine

9. Blood flow to the site9. Blood flow to the site

10. Intestinal bacteria and gastrointestinal enzyme level10. Intestinal bacteria and gastrointestinal enzyme level

11. General condition of the patient:11. General condition of the patient:

Comatose decrease motility thus affecting absorptionComatose decrease motility thus affecting absorption

12. Drug formulation: whether it is a slow release or 12. Drug formulation: whether it is a slow release or other formother form

Factors affecting pulmonary Factors affecting pulmonary

absorptionabsorption

1.1. Solubility of the drug in the bloodSolubility of the drug in the blood

2.2. Particle sizeParticle size

Large particles are deposited in the nasal tract Large particles are deposited in the nasal tract > > 5 5 microns; 2microns; 2--5 micron particles are deposited mainly 5 micron particles are deposited mainly in the in the tracheabronchialtracheabronchial region; while particles less region; while particles less than 1 micron penetrate into the alveolar sacs and than 1 micron penetrate into the alveolar sacs and absorbed into the bloodabsorbed into the blood

3. Water solubility3. Water solubility

High water solubility volatile drugs are absorbed in the High water solubility volatile drugs are absorbed in the nasal tract; while low water solubility drugs will nasal tract; while low water solubility drugs will reach the bronchioles to alveolireach the bronchioles to alveoli

Airway anatomyAirway anatomy

bronchial tree

trachea

diffusion distance: ~20 mm total gas exchange area: ~80 m2

diffusion distance blood/air: ~20 mm total exchange gas exchange area: ~80 m2

trachea

bronchial tree

alveoli

capillaries

Airway anatomyAirway anatomy

Factors affecting dermal absorptionFactors affecting dermal absorption

1. Condition of the skin: Stratum 1. Condition of the skin: Stratum corneumcorneum serves as the main serves as the main barrier. When abraded, increased absorption will resultbarrier. When abraded, increased absorption will result

2. Skin permeability coefficient2. Skin permeability coefficient

This represents the rate at which a particular drug penetrates tThis represents the rate at which a particular drug penetrates the he skinskin

3. Body region3. Body region

Not all regions of the body have the same skin thickness.Not all regions of the body have the same skin thickness.

Forehead versus palmForehead versus palm

4. Lipid solubility4. Lipid solubility

The more lipid soluble the drug is the more it will be absorbedThe more lipid soluble the drug is the more it will be absorbed

5. Skin hydration5. Skin hydration

Rate of AbsorptionRate of Absorption

The rate of absorption may be of toxicological importanceThe rate of absorption may be of toxicological importancebecause it is a major determinant of the peak plasma because it is a major determinant of the peak plasma concentration and, therefore, the likelihood of acute toxic concentration and, therefore, the likelihood of acute toxic effects. Transfer of chemicals from the gut lumen, lungs, or effects. Transfer of chemicals from the gut lumen, lungs, or skin into the general circulation involves movement across cell skin into the general circulation involves movement across cell membranes, and membranes, and simple passive diffusion of the unionized simple passive diffusion of the unionized molecule down a concentration gradient is the most molecule down a concentration gradient is the most

important mechanismimportant mechanism. Lipid. Lipid--soluble molecules tend to cross soluble molecules tend to cross cell membranes easily and are absorbed more rapidly than cell membranes easily and are absorbed more rapidly than waterwater--soluble ones. The gut wall and lungs provide a large and soluble ones. The gut wall and lungs provide a large and permeable surface area and allow rapid absorption; in contrast permeable surface area and allow rapid absorption; in contrast the skin is relatively impermeable and even highly lipidthe skin is relatively impermeable and even highly lipid--soluble chemicals can enter only slowlysoluble chemicals can enter only slowly

The lipid solubility and rate of absorption depend on the extentThe lipid solubility and rate of absorption depend on the extent of of ionization of the chemical. Compounds are most absorbed ionization of the chemical. Compounds are most absorbed from regions of the gastrointestinal tract at which they are leafrom regions of the gastrointestinal tract at which they are least st ionized. Weak bases are not absorbed from the stomach, but ionized. Weak bases are not absorbed from the stomach, but are absorbed from the duodenum which has a higher pH, are absorbed from the duodenum which has a higher pH, whereas weak acids are absorbed from the stomach. The rate whereas weak acids are absorbed from the stomach. The rate of absorption can be affected by the vehicle in which the of absorption can be affected by the vehicle in which the compound is given, because compound is given, because rapid absorption requires the rapid absorption requires the establishment of a molecular solutionestablishment of a molecular solution of the chemical in the of the chemical in the gut lumen. Extremely lipid soluble compounds, such as gut lumen. Extremely lipid soluble compounds, such as dioxins, may be only partially absorbed, because they do not dioxins, may be only partially absorbed, because they do not form a molecular solution in the aqueous phase of the form a molecular solution in the aqueous phase of the intestinal contents.intestinal contents.

Extent of AbsorptionExtent of Absorption

The extent of absorption is important in determining the total The extent of absorption is important in determining the total body exposure or internal dose, and therefore is an important body exposure or internal dose, and therefore is an important variable during chronic toxicity studies and/or chronic human variable during chronic toxicity studies and/or chronic human exposure. The extent of absorption depends on exposure. The extent of absorption depends on the extent to the extent to which the chemical is transferred from the site of which the chemical is transferred from the site of

administration into the local tissueadministration into the local tissue, and , and the extent to which the extent to which it is metabolized or broken down by local tissuesit is metabolized or broken down by local tissues prior to prior to reaching the general circulation. An additional variable reaching the general circulation. An additional variable affecting the extent of absorption is affecting the extent of absorption is the rate of removal from the rate of removal from the site of administrationthe site of administration by other processes compared with by other processes compared with the rate of absorptionthe rate of absorption

Chemicals given Chemicals given via via the gastrointestinal tract may be the gastrointestinal tract may be subject to a wide range of pH values and subject to a wide range of pH values and metabolizing enzymes in the gut lumen, gut wall, and metabolizing enzymes in the gut lumen, gut wall, and liver before they reach the general circulation. The liver before they reach the general circulation. The initial loss of chemical prior to it ever entering the initial loss of chemical prior to it ever entering the blood is termed blood is termed firstfirst--pass metabolism or prepass metabolism or pre--systemic metabolismsystemic metabolism; it may in some cases remove ; it may in some cases remove up to 100% of the administered dose so that none of up to 100% of the administered dose so that none of the parent chemical reaches the general circulation. the parent chemical reaches the general circulation. The intestinal lumen contains a range of hydrolytic The intestinal lumen contains a range of hydrolytic enzymes involved in the digestion of nutrients. The enzymes involved in the digestion of nutrients. The gut wall can perform similar hydrolytic reactions and gut wall can perform similar hydrolytic reactions and contains enzymes that can oxidize many drugscontains enzymes that can oxidize many drugs

FIRST PASS EFFECT

Intestinal vs. gastric absorption

Absorption and BioavailabilityAbsorption and Bioavailability

Irrespective of the reason that is responsible for the incompletIrrespective of the reason that is responsible for the incomplete e absorption of the chemical as the parent compound, it is absorption of the chemical as the parent compound, it is essential that there is a parameter which defines the extent of essential that there is a parameter which defines the extent of transfer of the intact chemical from the site of administration transfer of the intact chemical from the site of administration into the general circulation. This parameter is the into the general circulation. This parameter is the bioavailabilitybioavailability, which is simply the fraction of the dose , which is simply the fraction of the dose administered that reaches the general circulation as the parent administered that reaches the general circulation as the parent compound. (The term bioavailability is perhaps the most compound. (The term bioavailability is perhaps the most misused of all kinetic parameters and is sometimes used misused of all kinetic parameters and is sometimes used incorrectly in a general sense as the amount of drug available incorrectly in a general sense as the amount of drug available specifically to the site of toxicity).specifically to the site of toxicity).

Extent of Absorption or BioavailabilityExtent of Absorption or Bioavailability

Dose

Destroyed

in gut

Not

absorbed

Destroyed

by gut wall

Destroyed

by liver

to

systemic

circulation

Bioavailability

Definition: the fraction of the administered dose reaching the systemic circulation and is thus a measure of first pass elimination

for i.v.: 100%for non i.v.: ranges from 0 to 100%

e.g. lidocaine bioavailability 35% due to destruction in gastric acid and liver

metabolism

Liver

Liver artery

Liver vein

Systemic

circulation

010

20

30

40

50

60

70

0 2 4 6 8 10

Plasma concentration

Time (hours)

i.v. route

oral route

Bioavailability (F)

(AUC)o

(AUC)iv

PrinciplePrinciple

For xenobiotics taken by routes other than the

iv, the extent of absorption and the

bioavailability must be understood in order to

determine whether a certain exposure dose

will induce toxic effects or not. It will also

explain why the same dose may cause toxicity

by one route but not the other.

Calculation of BioavailabilityCalculation of Bioavailability

The fraction absorbed as the intact compound or bioavailability The fraction absorbed as the intact compound or bioavailability ((FF) is ) is

determined by comparison with intravenous (determined by comparison with intravenous (i.vi.v.) dosing (where .) dosing (where F =F = 1 by 1 by

definition). The bioavailability can be determined from the areadefinition). The bioavailability can be determined from the area under the under the

plasma concentrationplasma concentrationtime curve (AUC) of the parent compound , or the time curve (AUC) of the parent compound , or the

percentage dose excreted in urine as the parent compound, percentage dose excreted in urine as the parent compound, i.e. i.e. for an oral for an oral

dose:dose:

2. Distribution2. Distribution

Distribution is the Distribution is the reversible transferreversible transfer of the of the

chemical between the general circulation and chemical between the general circulation and

the tissues. Irreversible processes such as the tissues. Irreversible processes such as

excretion, metabolism, or covalent binding are excretion, metabolism, or covalent binding are

part of elimination and do not contribute to part of elimination and do not contribute to

distribution parameters. The important distribution parameters. The important

distribution parameters relate to the rate and distribution parameters relate to the rate and

extent of distribution.extent of distribution.

100-fold increase in free pharmacologically

active concentration at site of action.

NON-TOXIC TOXIC

Alter plasma binding of chemicals

1000 molecules

% bound

molecules free

99.9 90.0

1001

Rate of DistributionRate of DistributionThe rate at which a chemical may enter or leave a tissue may be The rate at which a chemical may enter or leave a tissue may be limited by two factors:limited by two factors:

(i) the ability of the compound to cross cell membranes and(i) the ability of the compound to cross cell membranes and

(ii) the blood flow to the tissues in which the chemical (ii) the blood flow to the tissues in which the chemical accumulates.accumulates.

The rate of distribution of highly waterThe rate of distribution of highly water--soluble compounds may soluble compounds may be slow due to their slow transfer from plasma into body be slow due to their slow transfer from plasma into body tissues such as liver and muscle; watertissues such as liver and muscle; water--soluble compounds do soluble compounds do not accumulate in adipose tissue. In contrast, very lipidnot accumulate in adipose tissue. In contrast, very lipid--soluble soluble chemicals may rapidly cross cell membranes but the rate of chemicals may rapidly cross cell membranes but the rate of distribution may be slow because they accumulate in adipose distribution may be slow because they accumulate in adipose tissue, and their overall distribution rate may be limited by tissue, and their overall distribution rate may be limited by blood flow to adipose tissueblood flow to adipose tissue

The rate of distribution is indicated by the distribution The rate of distribution is indicated by the distribution

rate constant, which is determined from the decrease rate constant, which is determined from the decrease

in plasma concentrations in early time points after an in plasma concentrations in early time points after an

intravenous dose. The rate constants refer to a mean intravenous dose. The rate constants refer to a mean

rate of removal from the circulation and may not rate of removal from the circulation and may not

correlate with uptake into a specific tissue. Once an correlate with uptake into a specific tissue. Once an

equilibrium has been reached between the general equilibrium has been reached between the general

circulation and a tissue, any process which lowers the circulation and a tissue, any process which lowers the

blood (plasma) concentration will cause a parallel blood (plasma) concentration will cause a parallel

decrease in the tissue concentration.decrease in the tissue concentration.

Factors affecting distributionFactors affecting distribution

1.1. Blood flowBlood flow

Drugs are readily distributed to highly Drugs are readily distributed to highly perfusedperfused tissue tissue like brain, liver, and kidneyslike brain, liver, and kidneys

2. Permeability limitations2. Permeability limitations

Many drugs do not readily enter the brain due to the Many drugs do not readily enter the brain due to the blood brain barrierblood brain barrier

3. Protein binding3. Protein binding

Acidic drugs are bound to the most abundant plasma Acidic drugs are bound to the most abundant plasma

protein (albumin); while basic drugs bind to protein (albumin); while basic drugs bind to --11--acid glycoprotein.acid glycoprotein.

4. Effect of pH4. Effect of pH

The pH of the blood or tissue affect the The pH of the blood or tissue affect the ionization of the drug and thus its distributionionization of the drug and thus its distribution

5. Age5. Age

In old people, Protein binding and body water In old people, Protein binding and body water will decrease, thus increasing the concentration will decrease, thus increasing the concentration of the drug per unit timeof the drug per unit time

6. Existence of storage sites:6. Existence of storage sites:

These include: Adipose tissue, plasma proteins, These include: Adipose tissue, plasma proteins, liver, kidneys, and boneliver, kidneys, and bone

Extent of DistributionExtent of Distribution

The extent of tissue distribution of a chemical depends The extent of tissue distribution of a chemical depends on the relative affinity of the blood or plasma on the relative affinity of the blood or plasma compared with the tissues. Highly watercompared with the tissues. Highly water--soluble soluble compounds that are unable to cross cell membranes compounds that are unable to cross cell membranes readily are largely restricted to readily are largely restricted to extracellularextracellular fluid fluid (about 13 L per 70 kg body weight). Water(about 13 L per 70 kg body weight). Water--soluble soluble compounds capable of crossing cell membranes (compounds capable of crossing cell membranes (e.g. e.g. caffeine, ethanol) are largely present in total body caffeine, ethanol) are largely present in total body water (about 41 L per 70 kg body weight).water (about 41 L per 70 kg body weight).

LipidLipid--soluble compounds frequently show soluble compounds frequently show

extensive uptake into tissues and may be extensive uptake into tissues and may be

present in the lipids of cell membranes and present in the lipids of cell membranes and

adipose tissue. adipose tissue.

. A factor which may further complicate the . A factor which may further complicate the

plasma/tissue partitioning is that some plasma/tissue partitioning is that some

chemicals bind reversibly to circulating chemicals bind reversibly to circulating

proteins such as albumin (for acid molecules) proteins such as albumin (for acid molecules)

and acid glycoprotein (for basic molecules).and acid glycoprotein (for basic molecules).

The extent and pattern of tissue distribution can The extent and pattern of tissue distribution can

be investigated by direct measurement of be investigated by direct measurement of

tissue concentrations in animals. Tissue tissue concentrations in animals. Tissue

concentrations cannot be measured in human concentrations cannot be measured in human

studies and, therefore, the extent of distribution studies and, therefore, the extent of distribution

in humans has to be determined based solely in humans has to be determined based solely

on the concentrations remaining in plasma or on the concentrations remaining in plasma or

blood after distribution is complete.blood after distribution is complete.

Chemicals appear to distribute in the body

as if it were a single compartment.

The magnitude of the chemicals

distribution is given by the apparent volume

of distribution (Vd).

volume of distribution

Volume of Distribution (Vd)

Volume into which a drug appears to distribute with a concentration equal to its plasma concentration after distribution is

complete

Amount of drug in body

Concentration in Plasma

Vd =

when a chemical shows a more extensive reversible when a chemical shows a more extensive reversible

uptake into one or more tissues the plasma uptake into one or more tissues the plasma

concentration will be lowered and the value concentration will be lowered and the value VVdd will will

increase. For highly lipidincrease. For highly lipid--soluble chemicals, such as soluble chemicals, such as

organochlorineorganochlorine pesticides, which accumulate in pesticides, which accumulate in

adipose tissue, the plasma concentration may be so adipose tissue, the plasma concentration may be so

low that the value of low that the value of VVdd may be many liters for each may be many liters for each

kilogram of body weight. This is not a real volume of kilogram of body weight. This is not a real volume of

plasma and therefore plasma and therefore VVdd is called the apparent volume is called the apparent volume

of distribution.of distribution.

It is an important parameter because extensive It is an important parameter because extensive

reversible distribution into tissues, which will reversible distribution into tissues, which will

give a high value of give a high value of VVdd , is associated with a , is associated with a

low elimination rate and a long halflow elimination rate and a long half--life . It life . It

must be emphasized that the apparent volume must be emphasized that the apparent volume

of distribution simply reflects the extent to of distribution simply reflects the extent to

which the chemical has moved out of the site which the chemical has moved out of the site

of measurement (the general circulation) into of measurement (the general circulation) into

tissues, and it does not reflect uptake into any tissues, and it does not reflect uptake into any

specific specific tissue(stissue(s).).