ABSORPTION, DISTRIBUTION

& EXCRETION OF TOXICANTS

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I TOXICANT – RECEPTOR INTERACTIONS (T

+ R TR RESPONSE)

A. Examples of some cell receptors and targets:

1. Cellular enzymes (activate or inhibit activity)

2. Receptor present in cellular membranes (plasma

membrane, etc.)

3. Cellular macromolecules (DNA, RNA, tubulin, etc.)

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B. Examples of Toxicant – Target Bonds [bond

strength (kcal/mole)]

1. Covalent (100) – sharing of electrons [irreversible

– uncommon]

2. Van der Waals (0.5) – weak electrostatic

attraction [common]- REV

3. Hydrogen (2-5) – stronger electrostatic attraction

[common]- REV

4. Ionic (5) – bond between oppositely charged

groups [common]- REV

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C. Structure Activity Relationship (lock and key

interaction)

Cell Surface Receptor

1. Affinity

2. Efficacy

3. Agonist effect

4. Antagonist effect

5. Competitive versus Noncompetitive effects

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• A. ADME are interrelated and toxic effect depends upon

ADME cycles – In most cases a toxicant’s effect is

proportional to the level of toxicant in blood since free

toxicant at the site of action (tissues) is in equilibrium with

free toxicant in the plasma. Therefore, a toxicant’s effect is

influenced by toxicokinetics or how this toxicant gets into

(absorption), around (distribution) and out of the body

(metabolism and excretion).

• It is important to understand that patient characteristics

such as age, tissue function (liver, kidney, etc.), living

habits (smoking, drinking, etc.) and nutrition can markedly

influence the pharmacokinetics of toxicants.

II ABSORPTION—DISTRIBUTION—METABOLISM—EXCRETION

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1. The onset of a toxicant’s action occurs when thattoxicant’s level of concentration at the site of action(receptors) is adequate to initiate and maintain T-Rinteraction. (consider absorption and distribution)

2. Toxicant levels at receptor site are determined bythe amount of exposure to toxicant (dose) and itscapacity to reach the most relevant site of action(bioavailability)

(i) Route of administration regulates the toxicantdelivery rate – The intravascular and intramuscularroutes of administration are fastest while oralabsorption is considered slow

B. Overview of toxicokinetics

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(ii) In general, metabolism of a toxicant

(liver) will decrease toxicant bioavailability.

The metabolism of biomolecules by liver

cells can activate or inactivate toxicity

(iii) Distribution of the toxicant regulates the

movement of the toxicant from the blood

to receptors. Toxicants can bind to tissue

sites after circulating in plasma (perhaps,

bound to plasma proteins)D TAD TA

(iv) Termination of toxic action occurs

when toxicant levels at the action site

fall below a minimum effective

concentration. Toxicants are excreted

by various tissues

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C. Expression of steady-state plasma level of repeatedly administered or repeat exposure toxicants

1. Css = F x D / CL x T

a. Css = steady-state plasma level (plateau)

b. F = bioavailability (% of drug absorbed)

c. D = dose

d. CL = clearance (elimination)

e. T = dose interval

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D. A toxicant may pass through a membrane / barrier by:

1. Passive transport (diffusion according to Fick’s

Law) -no E req’d

a. Simple Diffusion – consider: hydrophobicity,

MW, ionization state

(i) Hendersen Hasselbalch

For acids: pKa – pH = log [nonionized]/[ionized]

For bases: pKa – pH = log [ionized]/[nonionized]

b. Filtration – relatively low MW (e.g., < 150- 300),

water soluble

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2. Specialized transport – toxicant transported with E expenditure

a. active transport

(i) carrier mediates this

(ii) transport is dose dependent

(iii) competition for carrier is possible

b. protein binding may reduce toxicant transport

c. ionization remains a factor for toxicant transport

d. facilitated diffusion resembles active transport except that the toxicant moves with rather than against its conc. gradient

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G. Absorption of Toxicants

1. Gastrointestinal Tract

a. mouth, esophagus, stomach, small intestines, large

intestines, rectum, common bile duct, portal blood

supply

b. absorption is a ‘dynamic’ process

(i) ionization state – note differing lumenal pH

through GI tract clinical management of poisoning;

pH change

(ii) anatomical factors – intestinal folds, villi,

microvilli can differ from individual to individual

(iii) GI carrier proteins – e.g., for iron, glucose,

purines or pyrimidines

(iv) lipid solubility and particle size

(v) modification by gut flora

(vi) liver enzyme transformations – P450 liver

enzymes differ from individual to individual;

P450 enzyme function can be induced or

inhibited

(vii) biliary addition / removal of molecules –

bile acid functions

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2. Lungs – the uptake of inhaled toxicants dependsupon pulmonary perfusion and also onphysiochemical properties of the toxicant

a. nasopharyngeal and oral access routes to lungs,bronchi, broncheoli, alveoli, tissue differences perindividual, lung disease prior to toxicant exposure

b. absorption is a ‘dynamic’ process

(i) ionization state – although… less of an issue

(ii) anatomical factors

(iii) lung carrier proteins

(iv) plasma solubility and particle size – blood to gaspartition coefficient

(v) perfusion vs. ventilation rates as limiting factorsfor toxic effects

3. Skin – the rate limiting barrier in the dermal

absorption of chemicals is the epidermis.

Stratum corneum is most important layer.

a. absorption is a ‘dynamic’ process

(i) hydration of skin

(ii) anatomical factors

(iii) skin barrier proteins

(iv) plasma / lymph solubility and particle size

(v) ionization state of the toxicant

H. Distribution of Toxicant

1. Rate of distribution to organs or tissues is

determined by blood flow and the rate of

diffusion out of the capillary bed (key factors;

blood flow, affinity)

a. Volume of Distribution – three

compartments; plasma water, interstitial

water, and intracellular water

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(i) Tissue binding

(ii) Lipid solubility

b. Tissue “Storage” of Toxicants – the depot release phenomena, the concept of primary distribution relative to redistribution

(i) Kidney / Liver

(ii) Bone

(iii) Fat

c. Barriers – blood / brain, blood / CSF, placental

I. Excretion of Toxicant – Urinary, Fecal, Expiratory

1. Urinary excretion: Renal glomerular filtration, Renal

tubule secretion and / or reabsorption processes

a. Glomerular filtration – considerations are rate

(GFR), bound or unbound toxicant particle size,

toxicant ionization state and lipid solubility,

presence or absence of renal disease

b. Renal tubular secretion / reabsorption – same

considerations as above with added consideration of

carrier proteins

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2. Fecal Excretion – Toxicants ingested but not

absorbed, Biliary excretions

a. Nonabsorbed

b. Biliary excretions –

(i) liver enzyme biotransformations

(ii) lipophilicity

(iii) hepatocellular transport into bile

(iv) bound or unbound toxicant particle size and

ionization state

(v) age and health of the exposed individual

c. Intestinal excretions

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It is apparent from the material presented in this chapter and the

previous chapters related to metabolism that the metabolism of

xenobiotics is complex, involving many enzymes; that it is susceptible to

a large number of modifying factors, both physiological and exogenous;

and that the toxicological implications of metabolism are important.

Despite the complexity, summary statements of considerable

importance can be abstracted:

- Phase I metabolism generally introduces a functional group into a

xenobiotic, which enables conjugation to an endogenous metabolite to

occur during phase II metabolism.

- The conjugates produced by phase II metabolism are considerably

more water soluble than either the parent compound or the phase I

metabolite(s) and hence are more excretable.

- During the course of metabolism, and particularly during phase I

reactions, reactive intermediates that are much more toxic than the

parent compound may be produced. Thus xenobiotic metabolism may

be either a detoxication or an activation process.

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As organisms evolved in complexity, several

consequences of increased complexity

compromised the efficiency of the passive

diffusion of toxic chemicals:

1. They increased in size.

2. Their surface area to body mass decreased.

3. Their bodies compartmentalized (i.e., cells,

tissues, organs).

4. They generally increased in lipid content.

5. They developed barriers to the external

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Three major routes of elimination culminate in the

specialized organs of elimination, the liver, kidneys,

and lungs.

The liver serves as a major organ at which lipophilic

materials are collected from the blood,

biotransformed to generally less toxic and more

polar derivatives, then eliminated into the bile.

The kidneys complement the liver in that these

organs collect wastes and other chemicals in the

blood through a filtration process and eliminate

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The respiratory membranes of the lungs are ideal for the

removal of volatile materials from the blood into expired

air. In addition to these major routes of elimination, several

quantitatively minor routes exist through which toxic

materials can be eliminated from the body. These include

the following:

1. Skin. Skin constitutes the largest organ in the human

body, and it spans the interface between the body and the

external environment. While the skin’s epidermis

constitutes a relatively impervious membrane across which

chemical elimination is difficult, the shear surface area

involved requires consideration of this organ as a route of

elimination. Volatile chemicals are particularly adept at

traversing the skin and exiting the body through this route.

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2. Sweat. Humans lose an average of 0.7 L of water per day

due to sweating. This loss of fluid provides a route for the

elimination of water-soluble chemicals.

3. Milk. Mother’s milk is rich in lipids and lipoproteins. Milk

thus serves as an ideal route for the elimination of both water-

soluble and fat-soluble chemicals from the mother’s body. For

example, the DDT metabolite DDE, the flame retardant mirex,

and the polychlorinated biphenyls (PCBs) often have been

detected in mother’s milk. While lactation may provide a benefit

to the mother by the elimination of toxic chemicals, transfer of

these toxicants to the suckling infant can have dire

consequences.

4. Hair. Growing hair can serve as a limited route through

which chemicals can escape the body. Pollutants such as mercury

and drugs such as cocaine have been measured in human hair,

and hair analyses is often used as a marker of exposure to such

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- Because the number of enzymes involved in phase I and phase

II reactions is large and many different sites on organic

molecules are susceptible to metabolic attack, the number of

potential metabolites and intermediates that can be derived from a

single substrate is frequently very large.

- Because both qualitative and quantitative differences exist

among species, strains individual organs, and cell types, a

particular toxicant may have different effects in different

circumstances.

- Because exogenous chemicals can be inducers and/or inhibitors

of the xenobiotic metabolizing enzymes of which they are

substrates; such chemicals may interact to bring about toxic

sequelae different from those that might be expected from any of

them administered alone.

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- Because endogenous factors also affect the enzymes of

xenobiotic metabolism, the toxic sequelae to be expected

from a particular toxicant will vary with developmental

stage, nutritional statue, health or physiological status, stress

or environment.

- Most enzymes involved in xenobiotic metabolism occur

as several isozymes, which coexist within the same

individual and, frequently, within the same subcellular

organelle.

An understanding of the biochemistry and molecular

genetics of these isozymes may lead to an understanding of

the variation among species, individuals, organs, sexes,

developmental stages.D TA

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