ToxicokineticsToxicokinetics Toxicokinetics is the study of the drug movement Toxicokinetics is the study of the drug movement

around the body (Absorption, Distribution, around the body (Absorption, Distribution, metabolism, and Elimination)metabolism, and Elimination)

Toxicokinetic data is best derived using radio labeled Toxicokinetic 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

Toxicodynamics is the study of toxic actions Toxicodynamics is the study of toxic actions of xenobiotic substances on living systems.of xenobiotic substances on living systems.

Toxicodynamics is concerned with processes Toxicodynamics 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

Toxicokinetic (TK) Toxicokinetic (TK) processesprocesses

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 fluid

fat

Secretory Structures

Bile

Kidney Lung

Bladder Alveoli

Urine Expired Air Secretions

body organs

softtissue bone

Gastrointestinal tract

Lung

feces

InhalationIngestion

distribution

Toxicokinetics (ADME)Toxicokinetics (ADME)

Toxicokinetics study four processes:Toxicokinetics 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 toxicokinetics of a chemical are determined The toxicokinetics 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 Toxicokinetics is important in predicting the Toxicokinetics is important in predicting the

plasma concentration of a drugplasma concentration of a drug

Toxicokinetics and toxicityToxicokinetics and toxicity

Toxicity depends on:Toxicity depends on: Duration and concentration of drugDuration and concentration of drug at the portal of entry at 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 perfused organs like brain, liver and are distributed in highly perfused 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 organochlorine compounds concentrated in adipose example is organochlorine 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 organochlorines affect the DNAExample, some organochlorines affect 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 the The term absorption describes the process of the transfer of the

parent chemical from the site of administration into the parent chemical from the site of administration into the general circulation, and applies whenever the chemical is general circulation, and applies whenever the chemical is administered administered via via an extravascular route (an extravascular route (i.e. i.e. not by direct not by direct intravascular injection).intravascular 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 ‘extent of absorption’ depending confusion in discussing the ‘extent of absorption’ depending on whether the data refer to the parent chemical, or to on whether the data refer to the parent chemical, or to metabolites or both (when radiolabeling is used). This metabolites or both (when radiolabeling is used). This confusion is resolved by the proper use of the term confusion is resolved by the proper use of the term bioavailabilitybioavailability (the fraction of the dose administered that (the fraction of the dose administered that reaches the general circulation as the parent compound) to reaches the general circulation as the parent compound) to describe the extent of absorption.describe the extent of absorption.

Mechanism of Membrane Permeation

1. Passive diffusion2. Active transport 3. Facilitated transport4. 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 filtrationPassive transport is affected by:Passive transport is affected by: Ability of the drug to dissolve in the lipid portion of the cell Ability of the drug to dissolve in the lipid portion of the cell

membranemembrane 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 100-200 amu which will allow drugs of 100-200 amu to passto pass

Presence of the drug in its nonionized formPresence of the drug in its nonionized form

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)

Flicks’s law and DiffusionFlicks’s law and Diffusion

Where;

dD/dt = rate of mass transfer across the membrane

K = constant (coefficient of permeability)A = Cross sectional area of membrane exposed

to the compoundC0 = Concentration of the toxicant outside the

membraneCi = 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 endocytosis; : occurs by endocytosis; 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

Pinocytes (cell drinking) in which very small Pinocytes (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

vascularized which allows for rapid absorptionvascularized which allows for rapid absorption2. 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 ionizability of the drug. This factor affects the ionizability 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 increase7. 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 intestine8. Absorbing surface area of the intestine8. Absorbing surface area of the intestine9. Blood flow to the site9. Blood flow to the site10. Intestinal bacteria and gastrointestinal enzyme level10. Intestinal bacteria and gastrointestinal enzyme level11. General condition of the patient:11. General condition of the patient:Comatose decrease motility thus affecting absorptionComatose decrease motility thus affecting absorption12. 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 blood2.2. Particle sizeParticle sizeLarge particles are deposited in the nasal tract Large particles are deposited in the nasal tract > > 5 5

microns; 2-5 micron particles are deposited mainly microns; 2-5 micron particles are deposited mainly in the tracheabronchial region; while particles less in the tracheabronchial 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 solubilityHigh 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 anatomybronchial 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 corneum serves as the main 1. Condition of the skin: Stratum corneum serves as the main barrier. When abraded, increased absorption will resultbarrier. When abraded, increased absorption will result

2. Skin permeability coefficient2. Skin permeability coefficientThis represents the rate at which a particular drug penetrates the This represents the rate at which a particular drug penetrates the

skinskin3. Body region3. Body regionNot 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 palm4. Lipid solubility4. Lipid solubilityThe more lipid soluble the drug is the more it will be absorbedThe more lipid soluble the drug is the more it will be absorbed5. 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 importance because 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-soluble molecules tend to cross . Lipid-soluble molecules tend to cross cell membranes easily and are absorbed more rapidly than cell membranes easily and are absorbed more rapidly than water-soluble ones. The gut wall and lungs provide a large and water-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 lipid-the 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 extent of The lipid solubility and rate of absorption depend on the extent 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 from regions of the gastrointestinal tract at which they are least ionized. Weak bases are not absorbed from the stomach, least ionized. Weak bases are not absorbed from the stomach, but are absorbed from the duodenum which has a higher pH, but 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 first-pass metabolism or pre-first-pass 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 incomplete Irrespective of the reason that is responsible for the incomplete 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 Extent of Absorption or BioavailabilityBioavailability

Dose

Destroyed in gut

Notabsorbed

Destroyed by gut wall

Destroyedby liver

tosystemiccirculation

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

0

10

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 (i.v.) dosing (where determined by comparison with intravenous (i.v.) dosing (where F =F = 1 by 1 by definition). The bioavailability can be determined from the area under the definition). The bioavailability can be determined from the area under the plasma concentration–time curve (AUC) of the parent compound , or the plasma concentration–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:

22 . .DistributionDistribution

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

100 1

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 water-soluble compounds may The rate of distribution of highly water-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; water-soluble compounds do tissues such as liver and muscle; water-soluble compounds do not accumulate in adipose tissue. In contrast, very lipid-not accumulate in adipose tissue. In contrast, very lipid-soluble chemicals may rapidly cross cell membranes but the soluble chemicals may rapidly cross cell membranes but the rate of distribution may be slow because they accumulate in rate of distribution may be slow because they accumulate in adipose tissue, and their overall distribution rate may be adipose tissue, and their overall distribution rate may be limited by blood flow to adipose tissuelimited by blood 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 flowDrugs are readily distributed to highly perfused tissue Drugs are readily distributed to highly perfused tissue

like brain, liver, and kidneyslike brain, liver, and kidneys2. Permeability limitations2. Permeability limitationsMany 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 barrier3. Protein binding3. Protein bindingAcidic 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 -1- -1- acid glycoprotein.acid glycoprotein.

4. Effect of pH4. Effect of pHThe 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 distribution5. Age5. AgeIn old people, Protein binding and body water In old people, Protein binding and body water

will decrease, thus increasing the will decrease, thus increasing the concentration of the drug per unit timeconcentration of 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 water-soluble compared with the tissues. Highly water-soluble compounds that are unable to cross cell membranes compounds that are unable to cross cell membranes readily are largely restricted to extracellular fluid readily are largely restricted to extracellular fluid (about 13 L per 70 kg body weight). Water-soluble (about 13 L per 70 kg body weight). Water-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).

Lipid-soluble compounds frequently show Lipid-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 studies and, therefore, the extent of distribution in humans has to be determined distribution in humans has to be determined based solely on the concentrations remaining based solely on the concentrations remaining in plasma or blood after distribution is in plasma or blood after distribution is complete.complete.

Chemicals appear to distribute in the

body as if it were a single

compartment.

The magnitude of the chemical’s

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 PlasmaVd =

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 lipid-soluble chemicals, such as increase. For highly lipid-soluble chemicals, such as organochlorine pesticides, which accumulate in organochlorine 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 VVd d , is associated with a , is associated with a

low elimination rate and a long half-life . It low elimination rate and a long half-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 tissue(s).specific tissue(s).