Toxicokinetics is the study of how the body processes toxic materials through absorption, distribution, metabolism and excretion (ADME). Absorption involves passage of toxicants across biological membranes, mainly through simple diffusion or specialized transport mechanisms. Distribution of toxicants through the body is determined by volume of distribution. Metabolism transforms toxicants into more water-soluble compounds through phase I (oxidation, reduction, hydrolysis) and phase II (conjugation) reactions. Excreted routes include renal excretion through urine and extra-renal excretion through bile, lungs, mammary glands and other secretions, terminating the toxicological effects.

1. “What the body does to the DRUG”
PHARMCOKINETICS
AMIR SOHAIL

2. Toxicokinetics (TK)
 It is the study of disposition of a Toxic Materials.
 The disposition of a toxic material includes the processes of ADME
 Absorption
 Distribution
 Metabolism
 Excretion

3. Importance of Toxicokinetics studies
It determines
 Route of administration?
 Dose???
 Onset of action???
 Time of effect/Duration of action???
 Frequency of toxic material administration to determine
nature of toxicity?????

4. Absorption
 The process by which toxic material proceeds from the site of
administration to the blood stream within the body.
 Necessary for the production of a toxic effect.

5.  The matrix of biological membrane is composed of
polar lipid molecules arranged in a bilayer.
Toxic Materials and Cell Membranes

6. Passage of Toxicant across biologic
membrane
Toxicants cross the biological membranes by;
 Simple transfer
Diffusion
Filtration
 Specialized Transport
Active Transport
Facilitated Transport
Pinocytosis

7. SIMPLE TRANSFER
Diffusion

8. SIMPLE TRANSFER
1. Diffusion
o Most important mean for lipid soluble and unionized toxicants
because they dissolve rapidly in lipoid matrix of membrane and thus
diffuse quickly.
o It is energy independent. Toxicant moves from a region of higher
conc. to region of lower conc. (along the conc. Gradient or downhill
movement) until equilibrium is attained.
o Rate of diffusion depends on the magnitude of concentration gradient across the
membrane and degree of lipid solubility.

9. SIMPLE TRANSFER

10. pH PARTITION HYPOTHESIS
 Toxicants are weak acids and weak Bases and exist in ionized and
unionized form at physiologic solution.
 The amount of toxicant that exist in ionized and unionized form
depends on its Pka and the pH of the fluid in which it is
dissolved.
 Pka value is a characteristic of toxicant and remain constant for
an acid and base so degree of ionization depends on pH of the
medium.
SIMPLE TRANSFER

11.  When the pH of fluid is same as the Pka value of toxicant the
ratio of ionized to unionized form is 1:1
 The relative amount of ionized and unionized toxicant in the body
fluid at a particular pH can be determined by Henderson-
Hasselbalch equation.
SIMPLE TRANSFER

12. FOR WEAK ACIDIC TOXICANTS
pka = pH + log
FOR WEAK BASIC TOXICANTS
pka = pH + log Conc. Of ionized Toxicant
Conc. Of unionized Toxicant
Henderson-Hasselbalch equation

13. SIMPLE TRANSFER
2. Filtration
 It is simple passage of toxicants through pores or channels in the
membranes.
 toxicants having smaller molecular weight <100 polar and non
polar substances.
 Driving force is hydrostatic pressure or the osmotic difference
across the membrane due to which water flow through the
aqueous pores. This passive bulk fluid movement carries or drag
solute molecules through the pores in the moving stream.

14. SIMPLE TRANSFER

15. Specialized Transport
1. Active Transport
 It is energy dependant and require carrier.
 Movement occurs against the concentration gradient.
2. Facilitated Transport
 It is carrier mediated transport that operates along the
concentration gradient.
3. Pinocytosis
 It is also minor transport mechanism involves engulfing
extracellular matrix with in segment of the cell membrane to form
saccules or vesicles.

16. Bioavailability
 "Fraction of a dose of toxicant that is absorbed
from its site of administration and reaches, in an
unchanged form, the systemic circulation."
 Bioavailability through IV is 100%. But less or equal to
100% for any other route of administration. The term
absolute bioavailability is used when the fraction
of absorbed toxicant is related to its IV bioavailability.

17. Factors affecting absorption of Toxicants
 Physiochemical Properties of toxicants.
 Nature and type of dosage form.
 Concentration and Volume.
 Route of administration.
 Blood flow to the site of administration.
 Area of absorbing surface.
 Disease state

18. TOXICANT DISTRIBUTION
 It is the process by which toxicant reversibly leave the blood
stream and enter the extra vascular fluids and tissues.

19.  The extent of distribution is measured by VOLUME OF
DISTRIBUTION.
 It is the volume of body fluid to which toxicant is distributed.

Volume of Distribution = Dose_________
Plasma Concentration
DISTRIBUTION

20. BINDING TO PLASMA PROTEINS
 BINDING TO PLASMA PROTEINS: Toxicants are transported in the
circulating blood in two forms Free form and Bound to Plasma Proteins.
 FREE FORM of toxicant is usually dissolved in Plasma water and
toxicologically active, diffusible and available for metabolism and excretion.
 BOUND TOXICANT with plasma protein are toxicologically inactive, non
diffusible and not available for metabolism or they cannot cross the cell
membrane because of larger particle size.
DISTRIBUTION

21. TOXICANT
METABOLISM/BIOTRANSFORATION
 It is the conversion of lipid soluble and non polar compound to polar
and water soluble compound.
 It causes conversion of an active toxicant to inactive or less active
metabolite called Inactivation.
 It causes the conversion to an active to more active metabolites called
as bio activation or toxicological activation.

22. SITES OF BIOTRANSFORMATION
 Liver is primary site for biotransformation, called hepatic metabolism.
 Other organs includes Kidney, Lungs, Intestine, Brain, Plasma. Metabolism in
other organs is called extra-hepatic metabolism.
 In the liver cells (Hepatocytes) metabolic activity happens majorly in Smooth
Endoplasmic Reticulum (SER), and minorly Cytosol, Mitochondria, Nuclear
envelop and Plasma membrane.

23. METABOLIZING ENZYMES
MICROSOMAL ENZYMES
 Enzyme present in these microsomes are called microsomal enzymes.
 Monoxygenesases, Glucuronyl transferase are important microsomal enzymes.
 Microsomal enzymes are inducible by drugs/toxicants, diet and other factors.
NON-MICROSOMAL ENZYMES
 Enzymes occurring in organelles other than endoplasmic Reticulum are called
non microsomal enzymes. They are present in Cytoplasm, Mitochondria.

24. PATHWAYS/PHASES OF
BIOTRANSFORMATION
 Two major pathways or phases
 Phase I (Oxidation, Reduction, Hydrolysis).
 Phase II (Conjugation Reactions).
1.OXIDATION
 They increase hydrophilicity of toxicant by introducing polar functional
group such as –OH.
 Oxidation reactions are catalyzed by microsomal enzymes. Some are
catalyzed by non microsomal enzymes including Aldehyde,
Dehydrogenises, and monoamine oxidase.

25. MIXED FUNCTION OXIDASES
 Most Important group of oxidative enzymes are microsomal monooxygenases
or Mixed Function Oxidases (MFO). These enzymes are mostly located in
hepatic endoplasmic reticulum.
 The most important component of MFO is Cytochrome P-450 enzymes,
because it binds to the substrate and activates oxygen.
 The isoenzymes CYP3A4 and CYP2DA carry out biotransformation of largest
number of drugs/toxicants.

26. 2. REDUCTION
 It is the addition of Hydrogen to the toxic molecule, thereby generate polar
functional group such as hydroxyl or amino group which will further undergo
Phase II reactions.
3. HYDROLYSIS
 They cause the cleavage of toxicant molecule by adding up a molecule of
water.
 The hydrolytic enzymes that metabolize toxicant act on endogenous substances
and their activity is not limited to liver.
PATHWAYS/PHASES OF
BIOTRANSFORMATION

27. PATHWAYS/PHASES OF
BIOTRANSFORMATION
 Phase II or conjugation reactions involve combination of toxicants or its phase
I metabolite with an endogenous substance to form a highly polar product,
which can be efficiently from body.
 In Phase II reactions conjugated molecule consist of 2 parts EXOCON and
ENDOCON
 The endocns are derived from Carbohydrates or amino acids and possess a
larger molecule of polar and ionic in nature.
1. GLUCURONIDATION
 It is conjugation of xenobiotic with Glucronic Acid. It is most common and
most important phase II reaction in vertebrates except cat and fish.

28.  The limited capacity of this pathway in cat may increase the duration of action,
toxicity of several lipid soluble xenobiotics such as aspirin.
2.SULPHATION
 It is the conjugation of xenobiotic with sulphate. It occur less commonly.
 Capacity for sulphation is limited in pigs but important in cats.
 Drugs and chemicals capable of forming sulphate conjugates includes Phenols,
Alcohols, Arylamine, N-Hydroxylamine.
PATHWAYS/PHASES OF
BIOTRANSFORMATION

29. 3. METHYLATION
 It is the conjugation of xenobiotic with methyl group (-CH3).
 These reactions are of lesser important but most important in biosynthesis.
 The metabolite formed are not polar or water soluble and may possess equal or
greater activity than the parent compound.
4. GLUTATHIONE CONJUGATION
 Conjugation with glutathione and mercapteuric acid is an important metabolic
pathway. Because they usually form conjugate with toxic compounds.
PATHWAYS/PHASES OF
BIOTRANSFORMATION

30. 5. ACETYLATION
 It is important pathway of metabolism for drugs. Drug conjugate with acetyl
group (-CH3CO).
 It is primary route of biotransformation for sulpha drugs.
 This pathway is lacking in dogs and foxes due to the deficiency of arylamine
acetyltransferases enzyme.
6. CONJUGATION WITH AMINO ACIDS
 It is the conjugation with amino acids. The most important reaction involves
conjugation with glycine, Glutamine in man and ornithine in birds. Drugs
metabolized through this pathway are salicylic acid, Nicotinic acids.
PATHWAYS/PHASES OF
BIOTRANSFORMATION

31. 7. CONJUGATION WITH THIOSULPHATE
 It is the conjugation of xenobiotics with thiosulphate and very much important
in detoxification of cyanide.
 It involves transfer of sulphar atom from the thiosuphate to the cyanide ion in
the presence of enzyme rhodanese to form inactive thiocynate. It is excreted
the in urine.
PATHWAYS/PHASES OF
BIOTRANSFORMATION

32.  It is the process by which toxicant or their metabolites are irreversibly
transferred from body to external environment.
 It is important for termination of toxicological action of toxicants.
 toxicants are excreted by several routes including the Kidney, Lungs, Biliary
system, Intestine, Semen, Milk, Sweat, Lacrimations or other body secretions.
 Excretion through kidney is called renal excretion and through other organs is
called extra-renal excretion.
EXCRETION OF TOXICANTS

33. 1. RENAL EXCRETION OF DRUGS
 It is the most important route of drug/toxicant excretion. Agents that are water
soluble, non volatile and small in molecular size are excreted in urine.
 Amount of toxicant or its metabolites excreted from urine mainly depend upon
three processes.
 Glomerular filtration.
 Tubular reabsorption.
 Tubular secretion.
 GLOMERULAR FILTERATION: It is non selective and unidirectional
process by virtue of which all non protein bound drugs/toxicants are filtered
through Glomerular membrane into the renal tubule.
EXCRETION OF TOXICANTS

34.  The driving force for filtration through the glomerulus is the hydrostatic force
of the blood flowing in the capillaries.
EXCRETION OF TOXICANTS

35.  Therefore glomerular filtration of toxicant depends mainly on its plasma
protein binding and renal blood flow. If blood to kidney is decreased due to
any reason the excretion of drug/toxicants may decreased.
2.TUBULAR REABSORPTION
 It is the process by which toxicant and their metabolites are transported from
tubular fluid back into the capillary network. It generally occurs after
glomerulus filtration of drugs/toxicants and take place all along the renal
tubules.
EXCRETION OF TOXICANTS

36. 3.TUBULAR SECRETION
 It is a carrier mediated process by which some drugs/toxicants or metabolites
are selectively secreted from blood into the tubular lumen.
EXCRETION OF TOXICANTS

37. EXCRETION OF TOXICANTS
1. EXTRA RENAL EXCRETION OF DRUGS
 Biliary Excretion
 Pulmonary Excretion
 Mammary Excretion
 Salivary Excretion
 Gastrointestinal Excretion
 Other routes (Skin, Sweat, Lachrymal fluid, Genital secretion,
Bronchial secretion)

38. THANKS