TOXICOKINETICS

WHAT IS TOXICOKINETICS?

• Deals with how a substance gets into the body and

what happens to it in the body.
• Deals with what the body does with a drug when
given a relatively high dose relative to the
therapeutic dose.
WHAT IS TOXICOKINETICS?

• Is the study of the modelling and mathematical

description of the time course of disposition
(absorption, distribution, biotransformation, and
excretion) of xenobiotics in the whole organism.
PROCESSES INVOLVED IN TOXICOKINETICS
1. Absorption — the substance
enters the body.
2. Distribution — the substance
moves from the site of entry to
other areas of the body.
3. Biotransformation — the body
changes (transforms) the
substance into new chemicals
(metabolites).
4. Excretion — the substance or its
metabolites leave the body.
FACTORS DETERMINING THE SEVERITY OF
TOXICITY

• Duration and concentration of a substance at the portal

of entry.
• Rate and amount of the substance that can be absorbed.
• Distribution in the body and concentration of the
substance at specific body sites.
• Efficiency of biotransformation and nature of the
metabolites.
FACTORS DETERMINING THE SEVERITY OF
TOXICITY

• Ability of the substance or its metabolites to pass

through cell membranes and come into contact with
specific cell components (for example, DNA).
• Amount and duration of storage of the substance (or
its metabolites) in body tissues.
• Rate and sites of excretion of the substance.
• Age and health status of the person exposed.
TOXICOKINETICS AND 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 hazard than a substance that is biotransformed into
a less toxic metabolite (detoxified).
TWO MAJOR MODELS
• Classic Toxicokinetics
• Physiologic Toxicokinetics
COMPARISON
CLASSIC TOXICOKINETICS PHYSIOLOGIC TOXICOKINETICS

• Compartment models • Tissue or organ compartments

• Cannot predict tissue • Can predict tissue concentrations
concentrations • Rate constants represent
• Rate constans are defined known/hypothesized biological
by data processes
CLASSIC TOXICOKINETICS

• One-compartment
• Two-compartment
• Multiple compartment
e.g. blood is a compartment
other compartments: adipose tissue, liver, kidney
ONE-COMPARTMENT MODEL

• e.g. aminoglycosides rapidly distribute into tissues

and fluids in the body
ONE-COMPARTMENT MODEL

• The half-life of the chemical that follows a one-

compartment model is simply the time required for
half of the chemical to be lost from the plasma. Only
few chemicals actually follow the simple, first-order,
one compartment model.
TWO-COMPARTMENT MODEL

• E.g. vancomycin and digoxin

TWO-COMPARTMENT MODEL
TWO-COMPARTMENT MODEL

• A half-life for a chemical whose kinetic behavior fits a

two-compartment model is often referred to as the
"biological half-life." This is the most commonly used
measure of the kinetic behavior of a xenobiotic.
MULTI-COMPARTMENT MODEL

• the one- and two-compartment models cannot

adequately describe the kinetics of a chemical within the
body since there may be several peripheral body
compartments to which the chemical may go, including
long-term storage.
• biotransformation and elimination of a chemical may not
be simple processes but subject to different rates as
blood levels change
APPARENT VOLUME OF DISTRIBUTION

• The apparent volume of distribution (VD) is the total

volume of body fluids in which a toxicant is
distributed.
• The VD is expressed in liters.
APPARENT VOLUME DISTRIBUTION
• If a toxicant is distributed only in the plasma fluid,
– the plasma concentration will remain HIGH and a LOW VD
• if a toxicant is distributed in all sites (blood plasma,
interstitial, and intracellular fluids)
– there is greater DILUTION in plasma concentration and a
HIGHER VD
• Binding in effect reduces the concentration of free toxicants
in the plasma or VD.
• Toxicants that undergo rapid storage, biotransformation, or
elimination further affect the VD.
• A chemical that has high affinity to tissues will have a
large VD
• If VD of a chemical is known, it can be used to
estimate the amount of drug remaining in the body
at anytime if the plasma concentration at that time is
known
• Xc = VdCp
CLEARANCE

• Rate of chemical elimination from the body in terms

of volume fluid containing the chemical that is
cleared per unit of time (ml/min)
• TOTAL BODY CLEARANCE – the sum of the clearances
by undividual eliminating organs
CLEARANCE

• High clearance = efficient and rapid removal

• Low clearance = less efficient and slow removal
ELIMINATION (EXCRETION)

• Elimination is used in a broader sense and includes

the removal of the absorbed xenobiotic through
metabolic pathways as well as through excretion.
• Excretion pertains to the elimination of the
xenobiotic and its metabolites by specific excretory
organs.
PRIMARY ROUTES/ORGANS FOR
EXCRETION
• Urinary system (urine)
• Gastrointestinal system (feces)
• Respiratory system (exhaled air)
PHYSIOLOGIC TOXICOKINETICS
• Advantages of Physiologic Toxicokinetics over Classic
– Can provide the time course of distribution of
xenobiotics to any organ or tissue
– Allow estimation of effects of changing physiologic
parameters on tissue concentrations
– Can predict the toxicokinetics of chemicals across
species by allometric scaling
– Accommodate complex dosing regimens
PHYSIOLOGIC TOXICOKINETICS

• Disadvantages are
– More information is needed
– Mathematics is difficult
– Values for parameters are often poorly defined
PHYSIOLOGIC TOXICOKINETICS

• Physiologic model
(laboratory animals)
– Simulation
– Basic unit is the
Lumped
Compartment
Toxicant leaves the vascular space at a certain venous concentration:
Cout = concentration of toxicant in the vascular space
PHYSIOLOGIC TOXICOKINETICS PARAMETERS

• Anatomical
– Used to physically describe the various compartments
– Size (volume)
• Physiologic
– Blood flow (blood flow rate Qt ml/min)
– Cardiac output or total blood flow rate(Qc)
– Alveolar ventilation rate (Qp)
– Renal or hepatic
 PHYSIOLOGIC TOXICOKINETICS PARAMETERS

• Thermodynamic
Total concentration of xenobiotic in tissue = conc. of free xenobiotic in that tissue
(Ct) = (Cf)
Assumptions:
1. Total and free concentrations are at equilibrium
2. Only free xenobiotic can be exchanged between the tissue
subcompartments
PHYSIOLOGIC TOXICOKINETICS PARAMETERS

• Transport
– Passive diffusion (Fick’s Law)
• First order process
– Thin membrane, large surface areas, large
concentration differences ; enhance diffusion
– Membrane trasnporters
PHYSIOLOGIC TOXICOKINETICS PARAMETERS

• Efflux transporters – limit toxicant penetration

– 2 limiting conditions:
• Perfussion limited (blood flow limited or flow limited)
• Diffusion limited (barrier limited)
PHYSIOLOGIC TOXICOKINETICS PARAMETERS

• Perfusion limited compartments

– Permeability coefficient is greater than the blood
flow rate to the tissue
– PA > Qt
PHYSIOLOGIC TOXICOKINETICS PARAMETERS

• Diffusion limited Compartments

– Uptake of a toxicant is governed by its diffusion or
transport across cell membrane barriers
– Permeability area product < blood flow
– PA <<Qt
SPECIALIZED COMPARTMENTS

• Lung
– Inhalation is a common route of exposure
• Liver
– Major organ for biotransformation of xenobiotics
• Blood
– Tissue compartment is linked by the circulatory
system
THANK YOU