TOKSIKOKINETIKA

ABSORBSI & DISTRIBUSI TOKSIKAN

Anjar Mahardian Kusuma, M. Sc., Apt
DISPOSITION OF TOXICANTS
 The disposition of a chemical or xenobiotic is defined as the
composite actions of its absorption, distribution, biotransformation,
and elimination
 Toxicants usually pass through a number of cells, such as the
stratified epithelium of the skin, the thin cell layers of the
lungs or the gastrointestinal (GI) tract, capillary
endothelium, and ultimately the cells of the target organ.
 The plasma membranes surrounding all these cells are
remarkably similar. The basic unit of the cell membrane is a
phospholipid bilayer composed primarily of
phosphatidylcholine and phosphatidylethanolamine
CELL MEMBRANES
 Phospholipids are amphiphilic, consisting of a hydrophilic
polar head and a hydrophobic lipid tail
 In membranes, polar head groups are oriented toward the
outer and inner surfaces of the membrane, whereas the
hydrophobic tails are oriented inward and face each other to
form a continuous hydrophobic inner space
 The thickness of the cell membrane is about 7–9 nm
 Numerous proteins are inserted or embedded in the bilayer,
and some transmembrane proteins traverse the entire lipid bilayer,
functioning as important biological receptors or allowing the
formation of aqueous pores and ion channel
Toxicants cross membranes either by passive processes in
which the cell expends no energy or by mechanisms in which the
cell provides energy to translocate the toxicant across its membrane.
Passive Transport
.
 Simple Diffusion
 Most toxicants cross membranes by simple diffusion,
following the principles of Fick’s law which establishes that
chemicals traverse from regions of higher concentration to
regions of lower concentration without any energy
expenditure
 Small hydrophilic molecules (up to about 600 Da) permeate
membranes through aqueous pores
 hydrophobic molecules diffuse across the lipid domain of
membranes (transcellular diffusion)
 Filtration
 When water flows in bulk across a porous membrane, any
solute small enough to pass through the pores flows with it.
 Passage through these channels is called filtration, as it involves
bulk flow of water caused by hydrostatic or osmotic force
 In renal glomeruli, a primary site of filtration, these pores are
relatively large (about 70 nm) allowing molecules smaller
than albumin (approximately 60 kDa) to pass through
Special Transport
 Active Transport
 Active transport is characterized by: (1) movement of
chemicals against electrochemical or concentration gradients,
(2) saturability at high substrate concentrations, (3)
selectivity for certain structural features of chemicals, (4)
competitive inhibition by chemical cogeners or compounds
that are carried by the same transporter, and (5) requirement
for expenditure of energy, so that metabolic inhibitors block
the transport process.
 Xenobiotic Transporters
 Transporters mediate the influx (uptake) or efflux of xenobiotics
 ATP-binding cassette (ABC) transporters, P-gp (P-glycoprotein)
this transporter functions as an efflux pump was the first member
 The second major family of such transporters is known as solute
carriers (SLCs), SLC families play important roles in the
disposition of endogenous compounds, including glucose,
neurotransmitters, nucleotides, essential metals, and peptides.
Additionally, there are several families that are vital to xenobiotic
disposition, regulating the movement of many diverse organic
anions and cations across cell membranes
 Facilitated Diffusion
 Facilitated diffusion applies to carriermediated transport that
exhibits the properties of active transport except that the
substrate is not moved against an electrochemical or
concentration gradient, and the transport process does not
require the input of energy; that is, metabolic poisons do not
interfere with this transport
 AdditionalTransport Processes
 Phagocytosis and pinocytosis are proposed mechanisms for
cell membranes flowing around and engulfing particles
ABSORPTION
 The process by which toxicants cross body membranes and
enter the bloodstream is referred to as absorption
 There are no specific systems or pathways for the sole
purpose of absorbing toxicants.
 Xenobiotics penetrate membranes during absorption by the
same processes as do biologically essential substances such as
oxygen, foodstuffs, and other nutrients
 The main sites of absorption are the GI tract, lungs, and skin
Absorption of Toxicants by the
Gastrointestinal Tract
 The GI tract is one of the most important sites where
toxicants are absorbed
 This site of absorption is also particularly relevant to
toxicologists because accidental ingestion is the most
common route of unintentional exposure to a toxicant
(especially for children) and intentional overdoses most
frequently occur via the oral route.
 Absorption of toxicants can take place along the entire GI
tract, even in the mouth and the rectum.
 a toxicant is an organic acid or base, it tends to be absorbed
by simple diffusion in the part of the GI tract where it exists
in its most lipid-soluble (nonionized) form
 One can determine by the Henderson–Hasselbalch equations
the fraction of a toxicant that is in the nonionized (lipid-
soluble) form and estimate the rate of absorption from the
stomach or intestine
 The mammalian GI tract has numerous specialized transport
systems (carrier-mediated) for the absorption of nutrients
and electrolytes
 Some xenobiotics are absorbed by the same specialized
transport systems, thereby leading to potential competition
or interaction.
 For example, 5-fluorouracil is absorbed by the pyrimidine
transport system , thallium utilizes the system that normally
absorbs iron , lead can be absorbed by the calcium transporter,
and cobalt and manganese compete for the iron transport
system
 The number of toxicants actively absorbed by the GI tract is
low; most enter the body by simple diffusion. Although lipid-
soluble substances are absorbed by this process more rapidly
and extensively than are water-soluble substances the latter
may also be absorbed to some degree
 The mechanism by which some lipid-insoluble compounds
are absorbed is not entirely clear. It appears that organic ions
of low molecular weight (<200) can be transported across the
mucosal barrier by paracellular transport, that is, passive
penetration through aqueous pores at the tight junctions or
by active transport
 particle size determines absorption and factors such as the
lipid solubility or ionization characteristics areless important.
For particles,
 size is inversely related to absorption such that absorption
increases with decreasing particle diameter
 Emulsions of polystyrene latex particles 22 μm in diameter
enter intestinal cells by pinocytosis, a process that is much more
prominent in newborns than in adults
 In addition to the characteristics of the compounds
themselves, there are numerous additional factors relating to
the GI tract itself that influence the absorption of
xenobiotics. These factors include pH, the presence of food,
digestive enzymes, bile acids, and bacterial microflora in the
GI tract, and the motility and permeability of the GI tract
Absorption of Toxicants by the Lungs
 Toxic responses to chemicals can occur from absorption
following inhalation exposure
 A major group of toxicants that are absorbed by the lungs are
gases (e.g., carbon monoxide, nitrogen dioxide, and sulfur
dioxide), vapors of volatile or volatilizable liquids (e.g.,
benzene and carbon tetrachloride), and aerosols
Gases and Vapors
 The absorption of inhaled gases takes place mainly in the lungs
 nose acts as a ―scrubber‖ for water-soluble gases and highly
reactive gases, partially protecting the lungs from potentially
injurious insults
 Absorption of gases in the lungs differs from intestinal
 First, ionized molecules are of very low volatility, so that they do
not achieve significant concentrations in normal ambient air.
Second, the epithelial cells lining the alveoli—that is, type I
pneumocytes—are very thin and the capillaries are in close
contact with the pneumocytes, so that the distance for a chemical
to diffuse is very short. Third, chemicals absorbed by the lungs are
removed rapidly by the blood, and blood moves very quickly
through the extensive capillary network in the lungs
 blood-to-gas partition coefficient, the concentration of chemical
in the blood and chemical in the gas phase
 amount of gas dissolved in a liquid is proportional to the
partial pressure of the gas in the gas phase at any given
concentration before or at saturation.
 Thus, the higher the inhaled concentration of a gas (i.e., the
higher the partial pressure), the higher the gas concentration
in blood, but the blood:gas ratio does not change unless
saturation has occurred
 increase in the respiratory rate or minute volume does not
change the transfer of such a gas to blood
 In contrast, an increase in the rate of blood flow increases the
rate of uptake of a compound with a low solubility ratio
because of more rapid removal from the site of equilibrium,
Aerosols and Particles
 The absorption of gases and vapors by inhalation is
determined by the partitioning of the compound between the
blood and the gas phase along with its solubility and tissue
reactivity
 In contrast, the important characteristics that affect
absorption after exposure to aerosols are the aerosol size and
water solubility of any chemical present in the aerosol.
 The site of deposition of aerosols and particulates depends
largely on the size of the particles
 In general, the smaller the particle, the further into the
respiratory tree the particle will deposit
 a major determinant of lung deposition, as particle size
decreases, the number of particles in a unit of space increases
along with the total surface area of the particles
 The mechanisms responsible for the removal or absorption of
particulate matter from the alveoli are less clear
 First, particles may be removed from the alveoli by a physical
process
 Second, particles from the alveoli may be removed by
phagocytosis
Absorption of Toxicants Through the
Skin
 Skin is the largest body organ and provides a relatively good
barrier for separating organisms from their environment
 Human skin comes into contact with many toxic chemicals,
but exposure is usually limited by its relatively impermeable
nature. However, some chemicals can be absorbed by the skin
in sufficient quantities to produce systemic effects
 to be absorbed a chemical must pass the barrier of the
stratum corneum and then traverse the other six layers of the
skin
 There are several factors that can influence the absorption of
toxicants through the skin, including: (1) the integrity of the
stratum corneum, (2) the hydration state of the stratum
corneum, (3) temperature, (4) solvents as carriers, and (5)
molecular size
 Overall, commonly-used laboratory animals are typically not
good models of human absorption of toxicants
Absorption of Toxicants after Special
Routes of Administration
 other routes of administration may also be used. The most
common routes are: (1) intravenous, (2) intraperitoneal, (3)
subcutaneous, and (4) intramuscular
 the blood flow to the injection site have important role
DISTRIBUTION
 After entering the blood by absorption or intravenous
administration, a toxicant is distributed to tissues throughout
the body.
 Distribution usually occurs rapidly
 The rate of distribution to organs or tissues is determined
primarily by blood flow and the rate of diffusion out of the
capillary bed into the cells of a particular organ or tissue
 The final distribution depends largely on the affinity of a
xenobiotic for various tissues
Volume of Distribution
 The volume of distribution (Vd) is used to quantify the
distribution of a xenobiotic throughout the body
 It is defined as the volume in which the amount of drug would need
to be uniformly dissolved in order to produce the observed blood
concentration
Storage of Toxicants in Tissues
 Plasma Proteins as Storage Depot
 only the free fraction of a chemical is in equilibrium
throughout the body
 The compartment where a toxicant is concentrated is
described as a storage depot
 Binding to plasma proteins is the major site of protein
binding, and several different plasma proteins bind
xenobiotics and some endogenous constituents of the body.
 albumin is the major protein in plasma and it binds many
different compounds
 Because of their high molecular weight, plasma proteins and
the toxicant
 the interaction of a chemical with plasma proteins is a
reversible processs bound to them cannot cross capillary
walls.
 interactions with other highly bound compounds. In
particular, severe toxic reactions can occur
 This interaction increases the equilibrium concentration of
the toxicant in a target organ, thereby increasing the
potential for toxicity
 Xenobiotics can also compete with and displace endogenous
compounds that are bound to plasma proteins
 Plasma protein binding can also give rise to species
differences in the disposition of xenobiotics
 Additional factors that influence plasma protein binding
across species include differences in the concentration of
albumin, in binding affinity, and/or in competitive binding of
endogenous substances.
 Liver and Kidney as Storage Depots
 The liver and kidney have a high capacity for binding many
chemicals
 the concentration of lead in liver is 50 times higher than the
concentration in plasma
 some proteins serve to sequester xenobiotics in the liver or kidney
 metallothionein (MT), a specialized metal-binding protein
 α2u-globulin This protein, which is synthesized in large quantities
only in male rats, binds to a diverse array of xenobiotics including
metabolites of d-limonene (a major constituent of orange juice
and 2,4,4-trimethylpentane (found in unleaded gasoline)
 Fat as Storage Depot
 There are many organic compounds that are highly stable and
lipophilic
 The lipophilic nature of these compounds also permits rapid
penetration of cell membranes and uptake by tissues, and it is
not surprising that highly lipophilic toxicants are distributed
and concentrated in body fat
 toxicants with a high lipid/water partition coefficient may be
stored in body fat, and higher amounts are likely to be
retained in obese individuals
 Bone as Storage Depot
 Compounds such as fluoride, lead, and strontium may be
incorporated and stored in the bone matrix.
 Skeletal uptake of xenobiotics is essentially a surface chemistry
phenomenon
 Foreign compounds deposited in bone are not sequestered
irreversibly by that tissue
 Toxicants can be released from the bone by ionic exchange at the
crystal surface and dissolution of bone crystals through
osteoclastic activity
 Ultimately, deposition and storage of toxicants in bone may or
may not be detrimental.
Blood–Brain Barrier
 Access to the brain is restricted by the presence of two
barriers: the blood–brain barrier (BBB) and the blood–
cerebral spinal fluid barrier (BCSFB)
 The BBB is formed primarily by the endothelial cells of blood
capillaries in the brain
 neither represents an absolute barrier to the passage of toxic
agents into the CNS, many toxicants do not enter the brain in
appreciable quantities because of these barriers
 The blood–brain barrier is not fully developed at birth, and
this is one reason why some chemicals are more toxic in
newborns than adults.
 kernicterus resulting from increased brain evels of bilirubin
in infants was noted earlier.
 Lipid solubility plays an important role in determining the
rate of entry of a compound into the CNS, as does the degree
of ionizatio
 Some xenobiotics, although very few, appear to enter the
brain by carrier-mediated processes
placental barrier
 The term placental barrier has been associated with the concept
that the main function of the placenta is to protect the fetus
against the passage of noxious substances from the mother
 the placenta is a multifunctional organ that also provides
nutrition for the conceptus, exchanges maternal and fetal
blood gases, disposes of fetal excretory material, and
maintains pregnancy through complex hormonal regulation
 To reach the fetus, toxins must traverse the apical and
basolateral membranes of the syncytiotrophoblast as well as
the endothelium of the fetal capillaries
Redistribution of Toxicants
 The most critical factors that affect the distribution of
xenobiotics are the organ blood flow and its affinity for a
xenobiotic
 chemicals may have a high affinity for a binding site (e.g.,
intracellular protein or bone matrix) or to a cellular
constituent (e.g., fat), and with time, will redistribute to
these high affinity sites
 persistent organic pollutants do not distribute rapidly to fat,
but accumulate selectively in adipose tissue over time