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Lecture 4
Lecture 4
Lecture 4
TOXICOKINETICS
Absorption
Non-compartment
Zero
First
Order of reaction
Quantitative model
Compartment
Physiological-based TK
Clearance
Half-life
Volume of distribution
Bioavailability
Active
Passive
Ingestion
Inhalation
Skin penetration
Parenteral
Distribution
Circulation
Adipose tissue
Highly perfused ogan
Blood-brain barrier
Metabolism
Phase 1
Phase 2
Toxicokinetics
Parameters
Membrane transportation
Excretion
Kidney
Lung
Feces
Saliva
Lactation
Sweating
Toxicodynamics
Dosage
Exposure
Plasma Site of
action
Conc.
Toxicokinetics
Toxic
Effects
Toxicodynamics
xenobiotic
EXTERNAL
MEMBRANE
BARRIERS
skin
G.I. tract
lungs
DISTRIBUTION
BLOOD PLASMA
TISSUES
depots
METABOLISM
PHASE-1
PHASE-2
EXCRETION
KIDNEYS
LIVER
lungs
saliva
sweat
breast milk
Disposition of Xenobiotics
Ingestion
Inhalation
Intravenous
Intraperitoneal
Subcutaneous
Gastrointestinal
tract
absorption
Intramuscular
Lung
Dermal
Liver
Blood and lymph
Bile
extracellular
fluid
fat
distribution
Kidney
Bladder
feces
Urine
Lung
Secretory
Structures
soft
tissue
Alveoli
Expired Air
body
organs
Secretions
bone
excretion
Toxicokinetics (ADME)
Toxicokinetics study four processes:
1.
Absorption
2.
Distribution
3.
Metabolism
4.
Excretion
Metabolism and excretion processes are
combined as a single process called
elimination
Important principles of
toxicokinetics
1.
2.
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).
Many chemicals will be metabolized or transformed during
their passage from the site of administration into the
general circulation, so that little parent chemical may
reach the general circulation, this raises the possibility of
confusion in discussing the extent of absorption depending on
whether the data refer to the parent chemical, or to metabolites
or both (when radiolabeling is used). This confusion is
resolved by the proper use of the term bioavailability (the
fraction of the dose administered that reaches the general
circulation as the parent compound) to describe the extent of
absorption.
Mechanism of Membrane
Permeation
1.
2.
3.
4.
Passive diffusion
Active transport
Facilitated transport
Pinocytosis and phagocytosis
2. Special transport
Two types of special transport mechanisms 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)
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
Airway anatomy
bronchial tree
trachea
Airway anatomy
trachea
alveoli
capillaries
bronchial tree
Rate of Absorption
The rate of absorption may be of toxicological importance
because it is a major determinant of the peak plasma
concentration and, therefore, the likelihood of acute toxic
effects. Transfer of chemicals from the gut lumen, lungs, or
skin into the general circulation involves movement across cell
membranes, and simple passive diffusion of the unionized
molecule down a concentration gradient is the most
important mechanism. Lipid-soluble molecules tend to cross
cell membranes easily and are absorbed more rapidly than
water-soluble ones. The gut wall and lungs provide a large and
permeable surface area and allow rapid absorption; in contrast
the skin is relatively impermeable and even highly lipidsoluble chemicals can enter only slowly
Extent of Absorption
The extent of absorption is important in determining the total
body exposure or internal dose, and therefore is an important
variable during chronic toxicity studies and/or chronic human
exposure. The extent of absorption depends on the extent to
which the chemical is transferred from the site of
administration into the local tissue, and the extent to which
it is metabolized or broken down by local tissues prior to
reaching the general circulation. An additional variable
affecting the extent of absorption is the rate of removal from
the site of administration by other processes compared with
the rate of absorption
FIRST PASS
EFFECT
Intestinal vs.
gastric
absorption
Destroyed
in gut
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
Dose
to
systemic
circulation
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 vein
Systemic
circulation
Liver
Liver artery
Plasma concentration
70
60
Bioavailability (F)
(AUC)o
(AUC)iv
i.v. route
50
40
oral route
30
20
Time (hours)
10
0
0
10
Principle
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 Bioavailability
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 concentrationtime curve (AUC) of the parent compound , or the
percentage dose excreted in urine as the parent compound, i.e. for an oral
dose:
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 important
distribution parameters relate to the rate and
extent of distribution.
% bound
90.0
molecules free
100
NON-TOXIC
TOXIC
Rate of Distribution
The rate at which a chemical may enter or leave a tissue may be
limited by two factors:
(i) the ability of the compound to cross cell membranes and
(ii) the blood flow to the tissues in which the chemical
accumulates.
The rate of distribution of highly water-soluble compounds may
be slow due to their slow transfer from plasma into body
tissues such as liver and muscle; water-soluble compounds do
not accumulate in adipose tissue. 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 their overall distribution rate may be limited by
blood flow to adipose tissue
4. Effect of pH
The pH of the blood or tissue affect the
ionization of the drug and thus its distribution
5. Age
In old people, Protein binding and body water
will decrease, thus increasing the concentration
of the drug per unit time
6. Existence of storage sites:
These include: Adipose tissue, plasma proteins,
liver, kidneys, and bone
Extent of Distribution
The extent of tissue distribution of a chemical depends
on the relative affinity of the blood or plasma
compared with the tissues. 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).
volume of distribution
Chemicals appear to distribute in the body
as if it were a single compartment.
The magnitude of the chemicals
distribution is given by the apparent volume
of distribution (Vd).