Lecture Notes-5-Absorption, Distribution, Excretion
Lecture Notes-5-Absorption, Distribution, Excretion
and Excretion of
Toxicants
PRESENTATION WEEK 3
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 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
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
H CO2
NH3
NH3 NH2
H
NH2
Special Transport:
For molecules transported, often very
rapidly, across plasma membranes and
even against concentration gradients
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
Organic-Anion Transporters
(OATPs) in liver and kidneys
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
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
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.
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.
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