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Lecture Notes-5-Absorption, Distribution, Excretion

The document discusses the absorption, distribution, and excretion of toxicants in the body. It details the processes involved in the transfer of chemicals into systemic circulation, their biotransformation, and elimination through various routes such as urine and feces. Additionally, it highlights factors affecting absorption and distribution, including cell membrane transport mechanisms and the role of different organs in storing and excreting toxicants.

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0% found this document useful (0 votes)
8 views34 pages

Lecture Notes-5-Absorption, Distribution, Excretion

The document discusses the absorption, distribution, and excretion of toxicants in the body. It details the processes involved in the transfer of chemicals into systemic circulation, their biotransformation, and elimination through various routes such as urine and feces. Additionally, it highlights factors affecting absorption and distribution, including cell membrane transport mechanisms and the role of different organs in storing and excreting toxicants.

Uploaded by

sdn8gtztfd
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Absorption, Distribution,

and Excretion of
Toxicants
PRESENTATION WEEK 3
Absorption, Distribution, and Excretion of Toxicants

 Absorption is the transfer of a chemical from the site of exposure,


usually an external or internal body surface, into the systemic
circulation.

 Toxicants are removed from the systemic circulation by


biotransformation, excretion, and storage at various sites in the
body.

 Excretion is the removal of xenobiotics from the blood and their


return to the external environment via urine, feces, exhalation, etc.
Absorption, Distribution, and Excretion of Toxicants

FIGURE 5–1 Routes of absorption, distribution, and excretion of toxicants in the


Absorption, Distribution, and Excretion of Toxicants

 If the fraction absorbed or the rate of absorption is low, a chemical may never
attain a sufficiently high concentration at a potential site of action to cause toxicity

 the distribution of a toxicant may be such that it is concentrated in a tissue other


than the target organ, thus decreasing toxicity;

 Biotransformation of a chemical may result in the formation of less toxic or more


toxic metabolites at fast or slow rate

 The more rapidly a chemical is eliminated from an organism, the lower will be its
concentration and hence its toxicity in target tissues
Absorption of Toxicants-Cell Membranes

Cells
The stratified epithelium of skin
The thin cell layers of lungs
The thin cell layers gastrointestinal tract
The capillary endothelium
The cells of the target organ or tissue

Membrane Transport
a) Passive transport
b) Specialized transport

FIGURE 5–2 Schematic model o a biological


Absorption of Toxicants-Cell Membranes

 Simple Diffusion
Chemicals flow from higher to lower concentration area (Fick’s Law)
 Paracellular Diffusion: Small hydrophilic molecules (smaller than
600 daltons [Da]) permeate membranes through aqueous pores
 Transcellular Diffusion: Hydrophobic molecules diffuse across the
lipid domain of membranes (ethanol absorption and diffusion)
 Octanol/water partition coefficient, P,
The ratio of the concentration of neutral compound in organic and
aqueous phases under equilibrium conditions.
 Filtration: Passage of water(flow) in bulk across a porous membrane, with
any solute small enough to pass through the pores with it.
Absorption of Toxicants-Cell Membranes
Absorption of Toxicants-Cell Membranes

The pH at which a weak organic


acid (pKa) or base (pKb) is 50%
ionized CO2H
pKa = 14 − pKb
CO2H CO2

H CO2

NH3

NH3 NH2

H
NH2

FIGURE 5–3 Effect of pH on the ionization of benzoic acid (pKa = 4)


and aniline (pKa = 5).
Absorption of Toxicants-Cell Membranes

Special Transport:
 For molecules transported, often very
rapidly, across plasma membranes and
even against concentration gradients

TABLE 5–1 Distribution of Specialized


Transport Systems in the Small
Intestine of Man and Animals
Absorption of Toxicants-Cell Membranes

 Facilitated Diffussion: Carrier mediated transport that exhibits the properties of


active transport but that the substrate is not moved against an electrochemical or
concentration gradient. Requires no energy
 Active Transport:(1) movement of chemicals against electrochemical or
concentration gradients
(2) Saturability, at high substrate concentrations, thus exhibiting a transport
maximum (Tm)
(3) Selectivity or certain structural features of chemicals
(4) Competitive inhibition by chemical antagonists or compounds that are carried
by the same transporter, and
(5) Requirement or expenditure of energy (often in the form of ATP),
Absorption of Toxicants-Cell Membranes-Energy-
dependent xenobiotic transporters

Human ABC
Transporters:
Gene Family Overview
and
Major Transporters
Involved
in Xenobiotic Disposition
Absorption of Toxicants-Cell Membranes-
Energy-dependent xenobiotic transporters
Major Members of the Human
Solute Carrier Transporter Families
Involved in Xenobiotic Disposition

43 SLC families & 300 genes


disposition of endogenous
compounds, including glucose,
neurotransmitters, nucleotides,
essential metals, and peptides.

Organic-Anion Transporters
(OATPs) in liver and kidneys

Peptide Transporters (PEPTs)

Multidrug and Toxin Extrusion


(MATE) transporters
Liver and Kidneys
Absorption of
Toxicants-
Absorption
The
Gastrointestinal
Tract
pH
physical
properties lipid
solubility
dissolution rate
presence of food,
digestive
enzymes, bile
acids, bacterial
microflora, and
the motility and
permeability of
the GI tract.
Absorption of Toxicants-The Gastrointestinal
Tract
 First Pass
The removal of chemicals before entrance into the systemic circulation is
referred to as pre-systemic elimination, or First-Pass effect
 Result on the amount absorbed into the GI cells,
 Biotransformation by the GI cells,
 and Extraction by the liver into bile (with or without biotransformation).
 Other Factors
 Heavy metal ions such as lead easily absorbed
when chelated (EDTA) due to increase lipophilicity
 Consumption of grapefruit can influence GI absorption Naringin

 Naringin, a Flavonoid that can increase absorption (though inhibition of MDR1)


or decrease absorption (through inhibition of OATPs) of numerous
pharmaceuticals
5mm

Absorption of Toxicants-The Lungs


2.5mm

Gases and Vapors created by liquid evaporation or solid


sublimation
Water soluble/highly reactive gases are absorbed by the 1mm
nose
In lung alveolar space equilibrium is reached (Henry’s Law
of partial pressures) 10-20nm
Solubility ratio = concentration in blood/concentration in
gas phase
Greater than 1 highly soluble and transferable to blood
Less than 1, less soluble
Blood/Tissue equilibrium
Aerosols and Particles: Aerosols are a colloid of liquid and
solid particles in the air.
The smaller the particles the further in to the pulmonary
system
Greater than 5mm absorbed/stopped at nasopharyngeal
Absorption of
Toxicants by
the Lungs
Removal
of Absorption Particles
a) Physical Process
Aspirated to the
tracheochodrial region/mouth
where swallowed
Phagocytosis by alveolar
macrophages
Lymphatic tissue
b) Removal by dissolution
and vascular transport is
inefficient
FIGURE 5–4 Schematic diagram of the absorption
c) Some dust particles stay and translocation of chemicals by lungs.
Absorption of Toxicants-
The Skin

FIGURE 5–5 Diagram of a cross-section o human


skin.
Absorption of Toxicants-
The Skin

The stratum corneum the outermost layer most important


Lipophilic compounds:
They are absorbed quickly;
Proportionally to their lipid solubility and
Inversely related to molecular weight.
Hydrophilic compounds:
They are absorbed more slowly across the stratum corneum
More likely to penetrate through dermal appendages/glands
Absorption of Toxicants-The Skin

Factors influencing
Inter-species differences in dermal
the absorption of toxicants
absorption
(1)Theintegrity of the stratum (1)The composition and thickness of the
corneum
stratum corneum
(2)Thehydration state of the stratum
(2)The nature of dermal appendages
corneum
(3)Cutaneous blood flow,
(3)Ambient temperature
(4)Biotransformation reactions
(4)Solvents as carriers
(5)The levels and patterns of xenobiotic
(5)Molecularsize (Absorption is
transporters.
increased by decreasing size)
Absorption of Toxicants-Special Routes of
Administration

 Intravenous – Introduced directly into the blood stream


The peritoneum,
 Intraperitoneal – Introduced into the peritoneal blood colored in blue

stream-passes through liver


 Subcutaneous – slower absorption but straight into circulation
 Intramuscular – slower absorption but straight into circulation
 First Pass effect (and biotransformation) may reduce toxicity
and potency for intraperitoneal administration
Distribution of Toxicants-Volume Distribution

 Vd is the volume in which the amount of drug would need to be


uniformly dissolved in order to produce the observed blood
concentration.
 Water is 60% body weight
 Intracellular water (inside the cell)
 Extracellular water (interstitial water and plasma water, outside the
cell)
Distribution in plasma water (no tissue) corresponds to low Vd
and high plasma concentration
Distribution throughout the body (tissue) corresponds to high Vd and low
Distribution of Toxicants-Volume Distribution

Estimates of the Size of the Major Compartments That Contribute to Volume


of Distribution
Distribution of Toxicants-Storage of Toxicants in
Tissues

Plasma Proteins as Storage


Depot
Albumin (major ligand)
Secondary globulins, lipoproteins,
and glycoproteins

Ligand interactions as a result of


hydrophobic forces,
hydrogen bonding, and
van der Waals Forces
Distribution of Toxicants-Storage of Toxicants in
Tissues

 Liver and Kidney as Storage Depots


 Fat as Storage Depot
Lipophilic toxicants
Ca5(PO4)3(OH)
 Bone as Storage Depot hydroxyapatit
e
surface chemistry phenomenon between the bone surface
of
the hydroxyapatite krystalls and the extracellular fluid
Distribution of Toxicants-Tissue Barriers

 Blood Brain Barrier


 tightly joined capillary endothelial cells
of the CNS
 capillaries in the CNS are surrounded by
glial cell processes (astrocytes)
 protein concentration in the interstitial
fluid of the CNS is much lower than in
other body fluids
 ATP-dependent transporters include
members o both ABC and SLC families
Distribution of Toxicants-Tissue Barriers

Blood–CerebrosSpinal Fluid Barrier


(BCSFB)

is found between the circulating blood and the


circulating CSF

Increased lipid solubility enhances the rate of


penetration of toxicants into the CNS,
whereas ionization greatly diminishes it.
Distribution of Toxicants-Tissue Barriers

Placenta Barrier
the placenta is a multi Functional organ that provides nutrition,
exchanges maternal and
fetal blood gases,
disposes of fetal excretory
material, and
maintains pregnancy through
complex hormonal regulation.

Chemicals, viruses/pathogens
traverse the placenta
(rubella, syphilis, proteins)
Excretion of Toxicants-Redistribution

Excretion
 Urinary Excretion by: glomerular filtration, tubular
excretion by passive diffusion, and active tubular secretion.
 A toxicant filtered at the glomeruli may remain in the tubular lumen
and be excreted with urine or may be reabsorbed across the tubular
cells o the nephron back into the bloodstream.
 Lipophilic toxicants are reabsorbed easily
 Ionized and hydrophilic are excreted by urine
 passive diffusion through the tubule.
 active secretion.
Excretion of Toxicants - Reabsorption

Many functions of the


kidney are
incompletely
developed at birth,
some xenobiotics are
eliminated slower in
newborns than in
adults and therefore
may be more toxic to
newborns.
FIGURE 5–7 Schematic model showing the
transport systems in the proximal tubule o
The clearance of
the kidney.
penicillin by premature
Excretion of Toxicants

Fecal Excretion
Many chemicals in feces directly transfer from blood into
the intestinal contents by passive diffusion.
Nonabsorbed Ingesta: Remaining non absorbed
nutrients, drugs etc.

30% to 42% of fecal dry matter originates from bacteria.

Biotransformation by intestinal flora favors reabsorption


rather than excretion
FIGURE 5–8 Schematic model
showing
Excretion of Toxicants- Reabsorption

Biliary Excretion
Nutrients and xenobiotics in portal venous blood from the GI
tract are available for uptake by the liver or passage into the
systemic circulation.

Liver extraction and biotransformation of toxicants

Once a compound is excreted into bile and enters the


intestine, it can be reabsorbed or eliminated with feces.

Intestinal microflora may hydrolyze glucuronide and sulfate


conjugates (polar), making them sufficiently lipophilic for
reabsorption and enterohepatic cycling
Treatment of dimethyl mercury poisoning by polar polythiol
resin to bind mercury preventing reabsorption
Excretion of Toxicants- Other Reabsorption
Elimination Routes

 Exhalation
Breath analyzer to determine the ethanol in the body
 Cerebrospinal Fluid

All compounds can leave CSF by its flow through arachnoid villi,
to the venous system (blood stream)
Lipid-soluble toxicants also can exit at the site of the BBB.
 Milk 1) mother to nursing baby; 2) animals to humans

Toxic agents are excreted into milk by simple diffusion.


Milk pH = 6.5 therefore basic compounds have higher concentration than acidic or
lipophilic
Lipid soluble diffuse from plasma with the 3-4% fat content of milk
 Sweat and Saliva

Toxic compounds excreted by sweat may cause dermatitis


Toxic compounds in saliva may be reabsorbed by the GI track.
Absorption and Effects of
Toxicants

Schematic representation of the disposition and toxic effects of


chemicals

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