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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.
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 and 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).
Caffeine
tubocurarine
Elimination
The parameter most commonly used to describe
the rate of elimination of a chemical is the
half-life . Most toxicokinetic processes are
first-order reactions, i.e. the rate at which the
process occurs is proportional to the amount of
chemical present. High rates (expressed as
mass/time) occur at high concentrations and
the rate decreases as the concentration
decreases; in consequence the decrease is an
exponential curve.
where CL is the ability to extract and remove irreversibly the compound from
the general circulation, and V the extent to which the compound has left the
general circulation in a reversible equilibrium with tissues.
Summary of Toxicokinetic
Parameters
3 mg 0.25 mg/L = 12 L
It is possible to have a Vd greater than the total body
water
A high Vd is an indication that one or both of two things
has occurred,
Clearance (Cl)
A ratio relating the rate of elimination of a chemical
from an appropriate reference fluid (usually plasma) to
its concentration in the same reference fluid.
Has the units of flow rate in volume cleared per unit
time (e.g., mL/min)
A clearance of 100 mL/minute of a chemical means that
100 mL of blood/plasma is completely cleared of the
compound in each minute .
Half-life (t1/2)
The time required for the concentration of a chemical in
the plasma to decrease by 50%.
This is a constant for all but zero-order kinetics. For
example, for a compound eliminated by first-order
kinetics, if the concentration at time 0 is 4 mg/L, and the
t1/2 is 6 hours, then at the end of 6 hours, the plasma
concentration will be (0.5 x 4 mg/mL =) 2 mg/L, and at
the end of the next 6 hours, the concentration will be
(0.5 x 2 mg/mL =) 1 mg/L, and so on.
Concentration
in
plasma
Time (hrs)
Classical toxicokinetics
The elimination of a chemical is said to follow a onecompartment model when the elimination phase of the
log concentration vs time curve is a straight line.
Conceptually, this is as though the chemical were
evenly distributed throughout a single body
compartment (e.g., total body water), and is eliminated
at a constant rate over time. That is, a constant
percentage of the chemical present is eliminated over
any given time period.
Log of
Plasma
Concentratio
n
Plasma
Concentratio
n
Time
Time
Alpha distribution
Log of Plasma
Concentration
Beta distribution
Time
Chronic Administration
The kinetic concepts and parameters of a single dose (as
discussed above) apply to chronic administration, but
the exposure has to allow for the fact that not all of
the previous dose(s) may have been eliminated when
the subsequent dose is given. Therefore, there may be
an increase in plasma concentration (and body load)
until an equilibrium is reached in which the rate of
elimination balances out the rate of input, in other
words, the daily dose is eliminated each day.
Saturation Kinetics
All the parameters described above relate to first-order
processes and, therefore, are independent of dose at
low doses. However, at high doses and/or during
chronic studies it is possible to overload or saturate
compoundprotein interactions. Under such
circumstances any increase in the concentration of the
compound cannot give a proportional (first-order)
increase in the rate of the process. When a process is
saturated the rate is at the maximum possible and is
essentially independent of concentration.
3. Metabolism
Oxidation
Anything that affects the activity of any one of the steps can affect
the way the body reacts to a given drug or other xenobiotic.
Examples of the various types of oxidation reactions are in the
textbook,
Reduction
Azo reduction reduction of an azo bond (N=N) to two
amines (NH2)
Nitro reduction reduction of a nitro group (NO2) to an
amine
Hydrolysis
Phase II reactions
Sulfation
Glucuronidation
Acetylation
Methylation
Glutathione conjugation
Species
Age (activity is generally lower in very young and aged
animals)
Sex (activity is generally higher in males than in females)
Genetics (remember slow versus fast acetylators)
Organ (activity of many enzymes is highest in the liver)
General health status (e.g., hepatic injury decreases
metabolic activity in the liver)
Diet (remember how fasting decreases the amount of
glutathione available for GST)
Previous exposure to other compounds
Non-competitive inhibition
May occur when an inhibitor binds to the same active site on the enzyme
as the substrate, but binds so tightly that it is effectively not released. Thus,
the binding site is permanently blocked.
May also occur when an inhibitor binds tightly (sometimes covalently) to a
different site on the enzyme than the active site. This can result in
conformational or affinity changes that effectively inactive the enzyme.
Non-competitive inhibition is generally not reversible. Therefore,
recovery takes much longer because it requires the synthesis of new
enzyme.
A special subset of non-competitive inhibition is suicide inhibition, in
which a compound binds to the active site of an enzyme and is
metabolized, but the product then binds irreversibly to the active site. An
example of this is the binding of organophosphate insecticides to the
enzyme acetylcholinesterase (AchE). This results in a prolonged inhibition
of AchE activity.
3. Pharmacogenetic factors
Some individuals may be deficient in some enzymes, regardless
of sex
4. Pregnancy
Hepatic metabolism of drugs is decreased in pregnancy
5. Nutritional status/ liver dysfunction
Malnutrition can cause a decreased level of some enzyme system
and liver dysfunction can lead to decreased metabolism
6. Bioactivation
Some drugs may be transformed to more toxic metabolites
7. Enzyme induction / inhibition
A result of this is either an increase in the metabolism or a
decrease in the drug metabolism
8. Changes in the kinetic mechanism: depending on whether the
concentration of drug is in the therapeutic or overdose range
4. Excretion
Excretion
The removal of materials from the body
Routes of excretion
1.