Principles and Practice of Toxicology PHA 441

Toxicokinetics

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Learning outcomes

➢ Differentiate between toxicokinetics and toxicodynamics

➢ Revision of the definitions related to pharmacokinetcs/toxicokinetics

➢ Explain and describe the four main areas related to toxicokinetics (ADME)

➢ Identify the factors affecting toxicity

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Toxicokinetics
It denotes the absorption, distribution, excretion,
and metabolism of toxins, toxic doses of
therapeutic agents, and their metabolites.

Toxicodynamics
It is used to denote the injurious effects of these
substances on body functions.
“It deals with the study of biochemical and physiological effects
of toxicant and their mechanism of action”

Although many similarities exist between the pharmacokinetics and toxicokinetics of most substances, there
are also important differences. The same caution applies to pharmacodynamics and toxicodynamics.

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Four processes are involved in toxicokinetics:
Absorption: the substance enters the body.
Distribution: the substance moves from the site of entry to other areas of the body.
Biotransformation: the body changes (transforms) the substance into new chemicals (metabolites).
Excretion: the substance or its metabolites leave the body.

The science of toxicology has evolved to include environmental and

occupational chemicals as well as drugs.
Toxicokinetics is thus the appropriate term for the study of the kinetics
of all substances at toxic dose/exposure levels.

Frequently the terms toxicokinetics, pharmacokinetics, or disposition

have the same meaning.
Disposition is often used in place of toxicokinetics to describe the
movement of chemicals through the body over the course of time, that
is, how the body disposes of a xenobiotic.
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➢ The apparent volume of distribution (Vd) is defined as the apparent volume into
which a substance is distributed in the body. A large Vd implies that the drug distributes from the blood to other

tissues, and is therefore not readily accessible to measures aimed at purifying the blood, such as hemodialysis. A small Vd implies that the drug is
retained within the blood or extracellular fluid rather than distributing into tissues. Examples of drugs with large volumes of distribution (>5 L/kg)
that are sometimes involved in dangerous overdoses include antidepressants, antipsychotics, antimalarials, opioids, propranolol, and verapamil.
Drugs with a relatively small Vd (<1 L/kg) include salicylate, acetaminophen, ethanol, phenobarbital, lithium, valproic acid, and phenytoin.

➢ Clearance is a measure of the volume of plasma that is cleared of drug per unit time.
The total clearance for most drugs is the sum of clearances via excretion by the kidneys and metabolism by the liver.

➢ The half-life of elimination (t1/2) is the time required for the blood or plasma chemical
concentration to decrease by one half.

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 Elimination
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Summary of the disposition of toxicants as determined by absorption, distribution, and excretion
in the body. Black lines represent major pathways of absorption into the body, blue designates
distribution, and green lines identify pathways of final excretion (elimination) from the body, with the
exception of enterohepatic circulation, which is designated in red.
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 Absorption
▪ The ability to be absorbed is essential for systemic
toxicity to occur.
▪ Some chemicals are readily absorbed and others
poorly absorbed.
▪ For example, nearly all alcohols are readily absorbed
when ingested, whereas there is virtually no
absorption for most polymers.
▪ The key factor in the quantitative assessment of
human health risk from chemical exposure is the
correct quantification of the amount of the chemical
substance passing through the bio-membrane(i.e.
skin) and thus actually entering the body.
▪ Without the Toxicokinetics study, usually 100%
Schematic model of a biological membrane
absorption is assumed, which may over-predict the
risks of systematic toxicity.
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 Distribution

▪ The distribution of toxicants and toxic metabolites throughout the body ultimately
determines the sites where toxicity occurs.
▪ A major determinant of whether or not a toxicant will damage cells is its lipid
solubility.
▪ If a toxicant is lipid-soluble it readily penetrates cell membranes.
▪ Many toxicants are stored in the body. Fat tissue, liver, kidney, and bone are the
most common storage depots.
▪ Blood serves as the main avenue for distribution.
▪ Lymph also distributes some materials.

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 Metabolism
▪ Metabolism also known as biotransformation, is a major factor in determining
toxicity.
▪ The products of metabolism are known as metabolites.
▪ There are two types of metabolism
➢ Detoxification is the process by which a xenobiotic is converted to a less
toxic form.
This is a natural defense mechanism of the organism.
Generally, the detoxification process converts lipid-soluble compounds to
polar compounds.
➢ Bioactivation is the process by which a xenobiotic may be converted to
more reactive or toxic forms.

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 Excretion

▪ The site and rate of excretion is another major factor affecting the toxicity of a
substance.
▪ The kidney is the primary excretory organ, followed by the gastrointestinal tract, and
the lungs (for gases).
▪ Substances and metabolites may also be excreted in sweat, tears, and milk.
▪ A large volume of blood serum is filtered through the kidney.
▪ Lipid-soluble toxicants are reabsorbed and concentrated in kidney cells.
▪ Impaired kidney function causes slower elimination of toxicants and increases their
toxic potential.

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Toxicokinetics may thus be different from pharmacokinetics, from a technological
perspective, in many ways.
Solubility
In view of the very high doses used in
toxicokinetics, one can readily encounter
solubility problems.
These may occur during dosage form
preparation and administration and also in
terms of drug solubility in the
gastrointestinal (GI) tract.
More seriously, perhaps, this could give rise
to drug precipitation in biological fluids and in
organs and tissues giving rise to toxicity that
may not be associated with the intrinsic
pharmacological or toxicological effects of
the drug.
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Stability
Compound stability may be influenced by
concentrations and amounts of substances used in
toxicology.
Traditionally, in toxicology and toxicokinetic
studies, drugs may be administered mixed with
feed, and this is realistic in terms of resources.
Dosing compounds in toxicology studies by gavage
doses is labor-intensive and expensive.
However, fine dispersion of drug with feed, with
possible storage over considerable periods in this
finely dispersed form, can give rise to drug
degradation problems.
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 Factors influencing Toxicity

1. Composition Of The Toxic Agent

2. Dose & Concentration
3. Route Of Exposure
4. Metabolism Of The Toxicant
5. State Of Health
6. Age & Maturity
7. Nutritional State
8. Gender
9. Genetics
10. Environmental Factors

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1. Composition of the toxic agent
➢ Physiochemical composition of toxicant: solubility, charge, hydrophobicity.
✓ Solid vs Liquid
✓ Poisoning is more with liquid and small particles (particle size)

2. Dose and concentration

➢ Most important factor:
e.g. acute ethanol exposure --- CNS depression chronic exposure----- liver cirrhosis.

3. Route of exposure
✓ Inhalation (breathing)
✓ Skin (or eye) contact.
✓ Swallowing (ingestion or eating)
✓ Injection (skin penetration)

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 Exposure: Pathways
❑ Routes and Sites of Exposure
➢ Ingestion (GIT), (first pass effect).

➢ Inhalation (Lungs): rapid absorption, because of

large alveolar surface area.

➢ Dermal/Topical (Skin), absorption varies with

area of application and drug formulation, but
usually absorption is slower than other routes.
➢ Injection
✓ Intravenous, intramuscular, intraperitoneal.
❑ Typical response of Routes and Sites of Exposure
✓ IV > inhalation > IP > IM> oral > topical.

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 Detoxification by the Liver
4. Metabolism of the toxicant

There are two types of metabolism

✓ Detoxification
✓ Bioactivation

CYP450 enzymes and elderly???

The detoxification of compounds by the liver typically involves two sets of chemical pathways:
1. Toxins are converted into less harmful chemicals by oxidation, reduction and hydrolysis reactions.
✓ These reactions are mediated by a group of enzymes known as the cytochrome P450 enzyme group.
✓ These conversions produce damaging free radicals, which are neutralized by antioxidants within the liver.
2. The converted chemical is then attached to another substance (e.g. cysteine) via a conjugation reaction
✓ This renders the compound even less harmful and also functions to make it water soluble.
✓ The water soluble compounds can now be excreted from the body within urine by the kidneys.

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5. Health Status

✓ Hepatic, renal insufficiency.

✓ Diarrhea or constipation may decrease or increase the time of contact between

chemical and absorptive site.

6. Age and maturity

✓ Chloramphenicol ….Grey baby syndrome
✓ Geriatric…
✓ Generalized decrease in blood supply to tissue….decrease in toxicity….(not always)
✓ P.O. drugs….absorption decrease.
✓ Diseases (hepatic, renal, CV) …. Decrease detoxification, excretion, distribution.

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7. Nutritional state
➢ Empty stomach or food contents (pH, high
fat,….)

✓ Ca2+ in milk and tetracycline (3 hours

interval between the ingestion of
tetracyclines and calcium prevents the
interaction).
✓ Fatty food increase absorption of
griseofulvin.
✓ Tyramine rich food and MAO inhibitors.
✓ Hypoalbuminemia: greater amount of
free drug.

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8. Gender

✓ Difference in absorption …..

✓ Difference in metabolism rate ….
✓ Differences in quantities of muscle
mass and fat tissue .… in IM
injection.
9. Genetics: (Genetic toxicology)
e.g.
✓ inter-individual variations
✓ G6PD deficiency…..protect RBCs
from oxidative damage, may
cause hemolytic anemia.

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10. Environmental Factors

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