The document discusses toxicokinetics and toxicodynamics. Toxicokinetics is the study of what the body does to toxicants, including absorption, distribution, metabolism, and excretion. Absorption depends on factors like solubility, molecular size, and transport mechanisms. Distribution is influenced by protein binding, pH, and storage sites. Metabolism transforms toxicants via phase I (oxidation, reduction, hydrolysis) and phase II (conjugation) reactions. Toxicodynamics examines what toxicants do to the body by interacting with receptors and inducing effects. Toxicity depends on factors like concentration, absorption rate, distribution, metabolism, and excretion rate.

1. Professor Dr. Najat A. Hasan (MB ChB, MSc, PhD
in Clinical Biochemistry, College of Medicine -
Alnahrain University, Baghdad. Iraq)

2. • Toxicokinetics is the study of the drug movement around
the body (it Determines the no. molecules that can reach the
receptors)
1. Uptake (absorption)
2. Transport (distribution)
3. Metabolism & transformation
4. Sequestration
5. Excretion
Elimination involve steps 3,4,5
• Toxicokinetic data is best derived using radio labeled dose
of the drug. This allows for following the fate of the drug,
metabolic products, distribution in the tissue, storage sites,
as well as its elimination.
• Unfortunately, these methods do not provide knowledge
about proportion of the drug left intact to its metabolites.
• TK is concerned with what the body does to the toxicant.

3. Toxicodynamics is the study of toxic actions of xenobiotic
substances on living systems.
-It is concerned with processes and changes that occur to
the drug at the target tissue that results in an adverse effect.
-TD determines the no. of receptors that can interact with
toxicants).It include
1. Binding
2. Interaction
3. Induction of toxic effects
Simply, TD is concerned with what the toxicant do to the
body

4. Toxicokinetics and toxicity
Toxicity depends on:
1. Duration and concentration of drug at the portal of entry
2. The rate and amount (extent) of drug absorbed; toxicity will
be low at slow absorption rates. This means that a highly
toxic drug that is poorly absorbed may have same hazard as
another with low toxicity but is highly absorbed.
3. The distribution of drug within the body; where most drugs
are distributed in highly perfused organs like brain, liver and
kidneys. However, in some cases, the organ in which the drug
is concentrated may not necessarily suffer the damage. An
example is organochlorine compounds concentrated in
adipose tissue while the target organ is the brain.

5. 4. The efficiency of biotransformation and nature of
metabolites; where, in some cases, a drug may be
transformed to a more toxic metabolite or a more
lipid soluble or water soluble metabolite, which
affects absorption and distribution
5. The ability of the drug to pass through cell
membranes and interact with cell constituents.
Example, some organochlorines affect the DNA
6. The amount and storage duration of the drug or its
metabolites in the tissue. These may induce toxicity
after a long time following exposure. Lead in bones
is an example
7. The rate and site of excretion; where the more
rapid the excretion, the less toxicity it will produce

6. Toxicokinetics
1. Absorption
The term absorption describes the process of the transfer of the
parent chemical from the site of administration into the
general circulation, and applies whenever the chemical is
administered via an extravascular route (i.e. not by direct
intravascular injection).
- the term bioavailability describes the extent of absorption
(the fraction of the dose administered that reaches the general
circulation as the parent compound).
- Uptake Barriers are:-
1. Cell membrane
2. Cell wall
3. Epithelial cells of GI tract
4. Respiratory surface (lung, gill, tracheae)
5. Body surface

7. Drugs are absorbed by the following processes
I. Passive transport
• This can occur by simple diffusion due to concentration
gradient. Uncharged molecules may diffuse along conc.
gradient until equilibrium is reached. No substrate
specificity
• By passage of drugs through the pores (of the kidney and
capillaries), i.e. by filtration
Passive transport is affected by:
1.Ability of the drug to dissolve in the lipid portion of the cell
membrane. Lipophilic chemicals may diffuse through the
lipid bilayer
2.The size of the drug, in case it is water soluble. Aqueous
pores are about 4Ao which will allow drugs of 100-70000
atomic mass weight(amu) to pass. Small MW < 0.4 nm (e.g.
CO, N20, HCN) can move through cell pores
3.Presence of the drug in its nonionized form.

8. Flicks’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 compound
C0 = Concentration of the toxicant outside the membrane
Ci = Concentration of the toxicant inside the membrane
t = Thickness of the membrane
dD/dt = K . A (Co - Ci) / t
•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)
First order rate diffusion, depends on

9. II. Special transport: Two types can be identified:
1. Active diffusion:
• Independent of or against conc. gradient
• Require energy
• Substrate –specific
• Rate limited by no. of carriers
Example: Ca-pump (Ca2+ -ATPase)
2. Facilitated diffusion: when a drug has a specific carrier
protein, and does not occur against 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+

10. 1. Types of cells at the specific site:
sublingual cells which are highly vascularized ,allows for
rapid absorption
2. Period of time that drugs remain at the site:
Drugs are poorly absorbed within the mouth because the
time a drug spends in the mouth is very short, while
high absorption can occur in the intestine due to the
long time a drug spends there
 Factors affecting gastrointestinal rate of absorption
III. Additional transport:
occurs by endocytosis; where :
Phagocytes (cell eating) engulf the solid large particles
suspended in the intracellular fluid
Pinocytes (cell drinking) in which very small suspended
particles or liquids are engulfed

11. 3. pH
This factor affects the ionizability of the drug.
The acidic nature of the fluid in the stomach
facilitates the absorption of weakly acidic
drugs, while both weakly acidic and basic
drugs are well absorbed in the small intestine
since the pH there is almost neutral
4. The concentration at the absorption site
5. Presence of food or binding substances:
These will decrease the concentration of the
free drug and thus will lower its absorption

12. 6. Rate of gastric emptying:
As emptying rate is decreased, absorption in the
stomach will increase
7. Gastrointestinal motility:
This will decrease the amount absorbed in the stomach
while increase the amount absorbed in the intestine
8. Absorbing surface area of the intestine
9. Blood flow to the site
10. Intestinal bacteria and gastrointestinal
enzyme level
11. General condition of the patient:
Comatose decrease motility thus affecting absorption
12. Drug formulation: whether it is a slow release or
other form

13. Factors affecting rate of pulmonary
absorption
1. Solubility of the drug in the blood
2. Particle size
Large particles are deposited in the nasal tract > 5
microns; 2-5 micron particles are deposited mainly
in the tracheabronchial region; while particles less
than 1 micron penetrate into the alveolar sacs and
absorbed into the blood
3. Water solubility
High water solubility volatile drugs are absorbed in
the nasal tract; while low water solubility drugs will
reach the bronchioles to alveoli

14. • diffusion distance blood/air: ~20 mm
• total exchange gas exchange area: ~80
m2
trachea
bronchial tree
capillaries
Airway anatomy
alveoli

15. Factors affecting rate of dermal absorption
1. Condition of the skin: Stratum corneum serves as the
main barrier. When abraded, increased absorption will
result
2. Skin permeability coefficient
This represents the rate at which a particular drug penetrates
the skin
3. Body region
Not all regions of the body have the same skin thickness:
Forehead versus palm
4. Lipid solubility
The more lipid soluble the drug is ,the more it will be absorbed
5. Skin hydration

16. Extent of Absorption
The extent of absorption is important in determining
the total body exposure or internal dose. The extent
of absorption depends on:
1. the extent to which the chemical is transferred
from the site of administration into the local tissue
2. the extent to which it is metabolized or broken
down by local tissues prior to reaching the general
circulation.
3. the rate of removal from the site of administration
by other processes compared with the rate of
absorption

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

19. Plasma
concentration
i.v. route (AUC)o
(AUC)iv
Time (hours)
bioavailability : defines the extent of transfer of the intact chemical
from the site of administration into the general circulation.
bioavailability, which is simply the fraction of the dose
administered that reaches the general circulation as the parent
compound. is thus a measure of first pass elimination
Bioavailability
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
Oral route

20. Principle
For xenobiotics taken by routes other than the iv, the
fraction absorbed as the intact compound or
bioavailability (F) is determined by comparison with
intravenous (i.v.) dosing (where F = 1 by definition). The
bioavailability can be determined from the area under
the plasma concentration–time curve (AUC) of the
parent compound , or the percentage dose excreted in
urine as the parent compound, i.e. for an oral dose:

22. 2. DISTRIBUTION
Distribution is the reversible transfer of the chemical
between the general circulation and the tissues.
Irreversible processes such as excretion, metabolism, or
covalent binding are part of elimination and do not
contribute to distribution parameters.
The rate and extent is limited by three factors:
(i) the ability of the compound to cross cell membranes ,
Many drugs do not readily enter the brain due to the
blood brain barrier
(ii) the blood flow to the tissues in which the chemical
accumulates.
The rate of distribution of highly H2O-soluble compounds
may be slow; In contrast, very lipid-soluble chemicals may
rapidly cross cell membranes but the rate of distribution
may be slow because they accumulate in adipose tissue,
and limited by blood flow to adipose tissue

23.  Highly water-soluble compounds that are unable to cross cell
membranes readily are largely restricted to extracellular fluid
(about 13 L per 70 kg body weight). Water-soluble compounds
capable of crossing cell membranes (e.g. caffeine, ethanol) are
largely present in total body water (about 41 L per 70 kg body
weight).
III. Protein binding :Acidic drugs are bound to the most abundant
plasma protein (albumin); while basic drugs bind to a-1- acid
glycoprotein
IV. Effect of pH
The pH of the blood or tissue affect the ionization of the drug and
thus its distribution
V. Age
In old people, Protein binding and body water will decrease, thus
increasing the concentration of the drug per unit time
VI. Existence of storage sites:
These include: Adipose tissue, plasma proteins, liver, kidneys, and
bone

24. The extent and pattern of tissue distribution can be investigated by
direct measurement of tissue concentrations in animals. Tissue
concentrations cannot be measured in human studies and,
therefore, the extent of distribution in humans has to be
determined based solely on the concentrations remaining in
plasma or blood after distribution is complete.
Volume Of Distribution
• 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 into which a drug appears to distribute with a concentration
equal to its plasma concentration after distribution is complete
Vd = Amount of drug in body/ Concentration in plasma

25.  when a chemical shows a more extensive reversible uptake
into one or more tissues, the plasma concentration will be
lowered and the value Vd will increase.
 For highly lipid-soluble chemicals, such as organochlorine
pesticides, which accumulate in adipose tissue, the plasma
concentration may be so low that the value of Vd may be
many liters for each kilogram of body weight.
 a high value of Vd , is associated with a low elimination rate
and a long half-life . It must be emphasized that the apparent
volume of distribution simply reflects the extent to which the
chemical has moved out of the site of measurement (the
general circulation) into tissues.
Vd = Amount of drug in body/ Concentration in plasma

26. Transport & Deposition
• Transport
• Blood
• Lymph, haemolymph
• Water stream in xylem
• Cytoplamic strands in phloem
• Deposition
Toxicant Target organs
Pb Bone, teeth, brain
Cd Kidney, bone, gonad
OC, PCB Adipose tissue,milk
OP Nervous tissue
Aflatoxin Liver
organochlorines(OC),
OP: Organic polutant
PCB: Polychlorinated Biphenyl

27. Metabolism & Transformation
• Evolved to deal with metabolites and naturally occurring toxicants
• Principle of detoxification:
1. Convert toxicants into more water soluble form (more polar &
hydrophilic)
2. Dissolve in aqueous/gas phases and eliminate by excretion
(urine/sweat) or exhalation
3. Sequestrate in inactive tissues (e.g bone, fat)
P450 system
• A heme-containing cytochrome protein located in ER, and is
involved in electron transport.
• Highly conservative, occur in most plants & animals
• Two phases of transformation
• May increase or decrease toxicity of toxicants after
transformation (e.g turn Benzo[a]pyrene into benzo[a]pyrene
diol epoxide, and nitroamines into methyl radicals)
• Is inducible by toxicants

28. Induction of P450
Aryl Hydrocarbon
Receptor
Toxicant
Toxicant-Receptor
Complex
Translocating
protein
m-RNA for CYP1A
hours
Bind at
Specific site

29. The major transformation reactions for xenobiotics are listed below
Phase I Transformation
• Hydrolysis
RCOO- R’ + H2O ---------> RCOO-H + R’-OH
• Oxidation
NADP NADP+
R-H --------------------------> R-OH + H2O
• Epoxidation
R-CH=CH-R’ -----------> R---CH +CH-R’
Oxidation reactions:
alcohol dehydrogenation
aldehyde dehydrogenation
alkyl/acyclic hydroxylation
aromatic hydroxylation
deamination
desulfuration
N-dealkylation
N-hydroxylation
N-oxidation
O-dealkylation
sulphoxidation
Reduction reactions:
azo reduction
dehalogenation
disulfide reduction
nitro reduction
N-oxide reduction
sulfoxide reduction

30. Phase I Transformation
• The three main Phase I reactions are oxidation, reduction, and
hydrolysis.
• Mixed Function Oxidase (MFO) System in smooth ER (Microsomes)
• In vertebrates, primarily found in liver parenchyma cells, but also
other tissues (e.g intestine, gill)
• In Phase I reactions, a small polar group (containing both positive
and negative charges) is either exposed on the toxicant or added
to the toxicant.
• Toxicants that have undergone Phase I biotransformation are
converted to metabolites that are sufficiently ionized, or
hydrophilic, to be either eliminated from the body without further
biotransformation or converted to an intermediate metabolite
that is ready for Phase II biotransformation.
• The intermediates from Phase I transformations may be
pharmacologically more effective and in many cases more toxic
than the parent xenobiotic.
• Add polar group(s) to increase hydrophilicity for Phase II
transformation

31. Phase II transformation
• Cytochrome P450 II enzyme systems in cytosol
• Covalent conjugation to water soluble endogenous metabloites
(e.g. sugars, peptides, glucuronic acid, glutathione, phosphates &
sulphate)
• Further increase hydrophilicity for excretion in bile, urine and
sweat
• The sites of glucuronidation reactions are substrates having an
oxygen, nitrogen, or sulfur bond.
• This includes a wide array of xenobiotics
as well as endogenous substances, such as
bilirubin, steroid and thyroid hormones
Important Phase II enzymes
• Glutathione S-transferases (GST)
• Epoxide Hydrolase (EH)
• UDP-glucuronosyltransferase (UDP-GTS)
• Sulfotransferase (ST).
The primary Phase II reactions :
• glucuronide
conjugation (most
important and common)
• sulfate conjugation
• acetylation
• amino acid conjugation
• glutathione conjugation
• methylation

32. Examples of Phase II Transformation
• Deamination
R-NH2 ---------------------------> R=O + NH3
• Dealkylation
R-CH2-CH3 ----------------------> R + CH3-CH2O
• Dehalogenation:
R-Cl ---------------------------------> R-H + Cl+
Glutathione-S-transferase (GST)
O
R------R’ ---- ------------> HO-R-SG
R-Cl ------- --------------> R-SG + Cl
GST
GST

33. Sequestration
• Animals may store toxicants in inert tissues (e.g. bone, fat, hair,
nail) to reduce toxicity
• Plants may store toxicants in bark, leaves, vacuoles for shedding
later on
• Lipophilic toxicants (e.g. DDT, PCBs) may be stored in milk at high
conc and pass to the young animals.
• Metallothionein (MT) or phytochelatin may be used to bind
metals
Excretion
• Gases (e.g. ammonia) and volatile toxicants (e.g. alcohol) may be
excreted from the gill or lung by simple diffusion.
• Water soluble toxicants (molecular wt. < 70,000) may be excreted
through the kidney by active or passive transport
• Conjugates with high molecular wt. (>300) may be excreted into
bile through active transport
• Lipid soluble and non-ionised toxicants may be reabsorbed
(systematic toxicity)