Download Toxicokinetics Lect.

Toxicokinetics
The sequence between exposure to a chemical
and the generation of an adverse effect can be
divided into two aspects
1. Toxicokinetics or the delivery of the
compound to its site of action
2. Toxicodynamics or the response at the
site of action.
The Toxicological Paradigm
Toxicokinetics
• Toxicokinetics is the quantitation of the time
course of toxicants in the body during the
processes of absorption, distribution,
biotransformation, and excretion or clearance
of toxicants. In other words, toxicokinetics is a
reflection of how the body handles toxicants
as indicated by the plasma concentration of
that xenobiotic at various time points
• The end result of these toxicokinetic processes
is a biologically effective dose of the toxicant.
Toxicodynamics
Toxicodynamics refers to the molecular,
biochemical, and physiological effects of
toxicants or their metabolites in biological
systems
These effects are result of the interaction of the
biologically effective dose of the ultimate (active)
form of the toxicant with a molecular target
Molecular Targets Concept
The toxic action of a chemical is a consequence
of the physical/chemical interaction of the active
form of that chemical with a molecular target
within the living organism
Molecular Targets Concept
Reaction Types;
Non Covalent Binding
Covalent Binding
Electron Transfer
Enzymatic Reaction
Outcomes;
Dysfunction
Destruction
Neoantigen Formation
Examples of Molecular Targets
Proteins Arylhydrocarbon (Ah) receptor—Dioxin
Hemoglobin—CO
Lipids—Carbon tetrachloride
DNA—Aflatoxin
The Toxicological Process
• Toxicokinetics is the study of the drug
movement around the body (Absorption,
Distribution, metabolism, and Elimination)
• 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
• Toxicokinetics is concerned with what the
body does to the toxicant
Disposition of Xenobiotics
Ingestion
Inhalation
Intravenous
Intraperitoneal
Subcutaneous
Gastrointestinal
trac t
Inhalation
Lung
Ingestion
Intravenous
Intramusc ular
Intraperitoneal
Subcutaneous
Gastrointestinal
tract
Dermal
Intramuscular
Lung
Dermal
Liver
Liver
Blood and lymph
Blood and lymph
Bile
Bile
feces
Kidney
Lung
Bladder
Alveoli
KidneyUrine
Bladder
feces
Urine
Secretory
Structures
extracellular
fluid
LungSecretions
ex tracellular
fluid
body
organs
soft
tissue
Expired Air
fat
bone
Secretory
Structures
body
organs
soft
tis sue
Alveoli
Expired Air
fat
Secretions
bone
• The toxicokinetics of a chemical are
determined by measuring the concentrations
of the chemical in blood at various times
following a single dose. The fundamental
parameters that define the rates and extents
of distribution and elimination are derived
from data following an intravenous or oral
dose.
Important principles of Toxicokinetics
•
The effect which a drug produces is
dependent on:
1. The dose
2. The concentration in the target organ
•
•
The kinetics of a drug may differ from
therapeutic dose to its toxic dose
Toxicokinetics is important in predicting the
plasma concentration of a drug
Toxicokinetics and Toxicity
Toxicity depends on:
• Duration and concentration of drug at the portal of
entry
• 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.
• 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.
• 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
• The ability of the drug to pass through cell
membranes and interact with cell
constituents. Example, some organochlorines
affect the DNA
• The amount and storage duration of the drug
or its metabolites in the tissue. These may
induce toxicity after a long time after
exposure. Lead in bones is an example
• The rate and site of excretion; where the
more rapid the excretion, the less toxicity it
will produce