2. Definition
• Toxicokinetics describes the rate of
a chemical enter the body and how
the compound metabolise and
excrete once it is in the body.
• Simply, how a substance gets into the
body and what happens to it in the
body.
3. • Toxicokinetics deals with what the body does
with a drug when given a relatively
high dose relative to the therapeutic dose.
• The science of toxicology has evolved to
include environmental and
occupational chemicals as well as drugs.
• Toxicokinetics is thus the appropriate term for
the study of the kinetics of all substances at
toxic dose/exposure levels.
4. some examples of how toxicokinetics of
a substance can influence its toxicity:
• Absorption — A highly toxic substance that is poorly
absorbed may be no more hazardous than a substance of
low toxicity that is highly absorbed.
• Biotransformation — Two substances with
equal toxicity and absorption may differ in how hazardous
they are depending on the nature of
their biotransformation. A substance that is biotransformed
into a more toxic metabolite (bioactivated) is a
greater hazardthan a substance that is biotransformed into
a less toxic metabolite (detoxified).
5. Difference between pharmacokinetics
and toxicokinetics
Pharmacokinetics
• It has been with us for many
years .
• Extensive collaboration with
pharmacology.
• Lower doses than
toxicokinetics
Toxicokinetics
• It is a far more recent
discipline.
• It need extensive
collaboration with
toxicologist, toxicokinetics
and pharmacokinetics.
• Much higher doses are used
6. Four processes are involved
in toxicokinetics:
• Absorption — the substance enters the body.
• Distribution — the substance moves from the
site of entry to other areas of the body.
• Biotransformation — the body changes
(transforms) the substance into
new chemicals(metabolites).
• Excretion — the substance or
its metabolitesleave the body.
8. • The ability to be absorbed is essential for
systemic toxicity to occur.
• Some chemicals are readily absorbed and
others poorly absorbed.
• For example, nearly all alcohols are
readily absorbed when ingested, whereas
there is virtually no absorption for most
polymers.
9. Absorption
• The key factor in the quantitative assessment
of human health risk from chemical exposure
is the correct quantification of the amount of
the chemical substance passing through the
bio-membrane(i.e,skin) and thus actually
entering the body.
• Without the TK study, usually 100%
absorption is assumed, which may over-
predict the risks of systematic toxicity.
10. Distribution
The distribution of toxicants and toxic
metabolites throughout the body
ultimately determines the sites where
toxicity occurs.
A major determinant of whether or not a
toxicant will damage cells is its lipid
solubility.
If a toxicant is lipid-soluble it readily
penetrates cell membranes.
11. Many toxicants are stored in the body.
Fat tissue, liver, kidney, and bone are
the most common storage depots.
Blood serves as the main avenue for
distribution.
Lymph also distributes some
materials.
12. Metabolism
• Metabolism, also known
as biotransformation, is a major factor in
determining toxicity.
• The products of metabolism are known
as metabolites.
• There are two types of metabolism -
1. Detoxification
2. Bioactivation.
13. • Detoxification is the process by which a
xenobiotic is converted to a less toxic form.
This is a natural defense mechanism of the
organism. Generally the detoxification process
converts lipid-soluble compounds to polar
compounds.
• Bioactivation is the process by which a
xenobiotic may be converted to more reactive
or toxic forms.
14. Excretion
The site and rate of excretion is another
major factor affecting the toxicity of a
substance.
The kidney is the primary excretory organ,
followed by the gastrointestinal tract, and
the lungs (for gases).
Substances and metabolites may also be
excreted in sweat, tears, and milk.
15. Excretion
• A large volume of blood serum is filtered
through the kidney.
• Lipid-soluble toxicants are reabsorbed
and concentrated in kidney cells.
• Impaired kidney function causes slower
elimination of toxicants and increases
their toxic potential
16. • Toxicokinetics may thus be
different from pharmacokinetics,
from a technological perspective,
in many ways .
• Solubility
• Stability
17. Solubility:
In view of the very high doses used in
toxicokinetics, one can readily encounter solubility
problems.
These may occur during dosage form preparation
and administration and also in terms of drug
solubility in the gastrointestinal (GI) tract.
More seriously, perhaps, this could give rise to drug
precipitation in biological fluids and in organs and
tissues giving rise to toxicity that may not be
associated with the intrinsic pharmacological or
toxicological effects of the drug.
18. Stability
Compound stability may be influenced by
concentrations and amounts of substances used in
toxicology.
Traditionally, in toxicology and toxicokinetic studies,
drugs may be administered mixed with feed, and
this is realistic in terms of resources.
Dosing compounds in toxicology studies by gavage
doses is labor-intensive and expensive.
However, fine dispersion of drug with feed, with
possible storage over considerable periods in this
finely dispersed form, can give rise to drug
degradation problems.
