Toxicokinetics studies

1. TOXICOKINETICS STUDIES
SUBMITTED BY- VIKAS GUPTA
M.PHARM [PHARMACOLOGY]

2. CONTENTS
• Introduction
• Dosage
• Important principles of toxicokinetic
• Drugs Absorbtion process
• Mechanism of Membrane Permeation
• Application of toxicokinetic studies

3. INTRODUCTION
• Toxicokinetic --Toxicokinetic is the study of the drug movement
around the body (Absorption, Distribution, metabolism, and
best derived using radio labeled dose of the drug. This allows for
drug, metabolic products, distribution in the tissue, storage sites, as
Unfortunately, these methods do not provide knowledge about
intact to its metabolites.TK is concerned with what the body does to

5. TOXICODYNAMICS
• Toxicodynamic; Toxicodynamic is the study of toxic actions of xenobiotic substances
on living systems . Toxicodynamic is concerned with processes and changes that
occur to the drug at the target tissue, including metabolism and binding that results in
an adverse effect . Simply, TD is concerned with what the toxicant to the body.

6. DOSAGE
• Exposure
• Toxic Effects
• Plasma Concentration
• .Site of action
• Toxicokinetic
• Toxicodynamic

7. TOXICOKINETIC (TK) PROCESSES
• ABSORPTION DISTRIBUTION
• METABOLISM EXCRETION
• EXTERNAL BLOOD
PLASMA
• PHASE-1 KIDNEYS
• MEMBRANE LIVER
• BARRIERS Xenobiotic
• Lungs skin
• TISSUES saliva
• PHASE-2 G.I. tract
• Sweat Lungs
• Depots Breast milk

8. TOXICOKINETIC (ADME)
Toxicokinetic study four processes:
• Absorption
• Distribution
• Metabolism
• Excretion
Metabolism and excretion processes are combined as a single process called elimination
The toxicokinetic of a chemical are determined by measuring the concentrations of the chemical in
plasma (usually) or 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.

9. IMPORTANT PRINCIPLES OF TOXICOKINETIC
The effect which a drug produces is dependent on:
• The dose
• The concentration in the target organ.
• The kinetics of a drug may differ from therapeutic dose to its toxic
dose.
• Toxicokinetic is important in predicting the plasma concentration of
a drug.

10. TOXICOKINETIC 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.

11. • 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

12. 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.

13. MECHANISM OF MEMBRANE PERMEATION
• Passive diffusion
• Active transport
• Facilitated transport
• Pinocytosis and phagocytosis

14. DRUGS ARE ABSORBED BY THE FOLLOWING
PROCESSES:
• Passive transport
• This can occur by simple diffusion due to concentration gradient or
• By passage of drugs through the pores (of the kidney and capillaries), i.e. by
filtration Passive transport is affected by;
• Ability of the drug to dissolve in the lipid portion of the cell membrane.
• The size of the drug, in case it is water soluble.
• Aqueous pores are about 4Ao which will allow drugs of amu to pass
Presence of the drug in its nonionized form

15. UPTAKE BY PASSIVE DIFFUSION
• Uncharged molecules may diffuse along conc. gradient until equilibrium is
reached No substrate specificity Small MW < 0.4 nm (e.g. CO, N20, HCN)
can move through cell pores Lipophilic chemicals may diffuse through the
lipid bilayer.
• First order rate diffusion, depends on Concentration gradient Surface area
(alveoli 25 x body surface) Thickness Lipid solubility & ionization
Molecular size (membrane pore size = 4-40 A, allowing MW of ,000 to pass
through)
•

16. FLICKS’S LAW AND DIFFUSION
dD/dt = KA (Co - Ci) / t
Where;
• dD/dt = rate of mass transfer across the membrane
• K = constant (coefficient of permeability)
• A = Cross sectional area of membrane exposed to the compound
• C0 = Concentration of the toxicant outside the membrane
• Ci = Concentration of the toxicant inside the membrane
• t = Thickness of the membrane

17. 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
• The rate of distribution is indicated by the distribution rate constant, which is determined from the decrease in plasma
concentrations in early time points after an intravenous dose. The rate constants refer to a mean rate of removal from the
circulation and may not correlate with uptake into a specific tissue. Once an equilibrium has been reached between the
general circulation and a tissue, any process which lowers the blood (plasma) concentration will cause a parallel
decrease in the tissue concentration.

18. FACTORS AFFECTING DISTRIBUTION
• Blood flow
• Drugs are readily distributed to highly perfused tissue like brain, liver, and kidneys
• 2. Permeability limitations
• Many drugs do not readily enter the brain due to the blood brain barrier
• 3. Protein binding
• Acidic drugs are bound to the most abundant plasma protein (albumin); while basic drugs bind toa-1-acidglycoprotein.
• 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

19. 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).
• Lipid-soluble compounds frequently show extensive uptake into tissues and may be
present in the lipids of cell membranes and adipose tissue..
• A factor which may further complicate the plasma/tissue partitioning is that some
chemicals bind reversibly to circulating proteins such as albumin (for acid molecules) and
acid glycoprotein (for basic molecules).
• The extent and pattern of tissue distribution can be investigated by direct measurement
of tissue concentrations in animals. Tissue concentrations cannot be measured in human
studies and, therefore, the extent of distribution in humans has to be determined based
solely on the concentrations remaining in plasma or blood after distribution is complete.

20. VOLUME OF DISTRIBUTION
• Chemicals appear to distribute in the body as if it were a single compartment.
• The magnitude of the chemical’s distribution is given by the apparent volume of distribution
(Vd).
• Volume of Distribution (Vd)
Volume into which a drug appears to distribute with a concentration equal to its plasma
concentration after distribution is complete Amount of drug in body Concentration in Plasma
Vd =when a chemical shows a more extensive reversible uptake into one or more tissues the
plasma concentration will be lowered and the value Vd will increase. For highly lipid-soluble
chemicals, such as organochlorine pesticides, which accumulate in adipose tissue, the plasma
concentration may be so low that the value of Vd may be many liters for each kilogram of body
weight. This is not a real volume of plasma and therefore Vd is called the apparent volume of
distribution.
• It is an important parameter because extensive reversible distribution into tissues, which will
give a high value of Vd , is associated with a low elimination rate and a long half-life . It must
be emphasized that the apparent volume of distribution simply reflects the extent to which the
chemical has moved out of the site of measurement (the general circulation) into tissues, and it
does not reflect uptake into any specific tissue(s).

21. APPLICATION OF TOXICOKINETICS STUDIES
TK is useful in the selection of
• Dose
• Dosing form
• alternating dosing route
• Evaluation of dosing mechanism
• Useful in setting safe dose level in clinical phases
• TK studies also used to reduce animal number.
• TK evaluation is very useful in drug development phase in both
scientific and regulatory perspective.