Absorption, distribution, metabolism & elimination

MKA2009©
11
ABSORPTION, DISTRIBUTION,ABSORPTION, DISTRIBUTION,
BIOTRANSFORMATION ANDBIOTRANSFORMATION AND
EXCRETION OF XENOBIOTICSEXCRETION OF XENOBIOTICS
Dr Mohd Khan AyobDr Mohd Khan Ayob
PPSKTMPPSKTM
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Toxicological ParadigmToxicological Paradigm
Exposure Internal
Dose
Biologically
Effective
Dose
Early
Biological
Effect
Altered
Structure &
Function
Disease
Absorption
Distribution
Biotransformation
Excretion
Storage
Toxicokinetics Toxicodynamics
What We do to the Chemical What the Chemical Does to Us
Susceptibility and
Modifying Factors
(Genetics and Nutritional Status)
Exposure Assessment Risk Assessment

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What is Toxicokinetics?What is Toxicokinetics?
 the study of "the study of "how a substance gets intohow a substance gets into
the body and what happens to it in thethe body and what happens to it in the
bodybody".".
 Four processesFour processes
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Interrelatedness of ADM(B)EInterrelatedness of ADM(B)E
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ToxicodynamicsToxicodynamics
 Toxicodynamics refers to the molecular,
biochemical, and physiological effects of
toxicants or their metabolites in biological
systems
 These effects are result of the interaction of the
biologically effective dose of the ultimate (active)
form of the toxicant with a molecular target
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Molecular Targets Concept
 The toxic action of a chemical is a consequence
of the physical / chemical interaction of the
active form of that chemical with a molecular
target within the living organism
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Examples of Molecular Targets
 Proteins
 Arylhydrocarbon(Ah) receptor—Dioxin
 Hemoglobin—CO
 Lipids—Carbon tetrachloride
 DNA—Aflatoxin
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Dose-Response Concept
 The magnitude of the toxic effect will be a
function of the concentration of altered
molecular targets, which in turn is related to the
concentration of the active form of the toxicant
(biologically effective dose) at the site where
the molecular targets are located.
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The Toxicological Process
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The Toxicological Process
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AbsorptionAbsorption
 the process whereby toxicants gainthe process whereby toxicants gain
entrance into the body.entrance into the body.
• Ingested and inhaled materials are stillIngested and inhaled materials are still
considered outside the bodyconsidered outside the body
 important factors affect of xenobioticimportant factors affect of xenobiotic
absorption.absorption.
• route of exposureroute of exposure
• concentration of the substance at the site ofconcentration of the substance at the site of
contactcontact
• chemical and physical properties of thechemical and physical properties of the
substancesubstance
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primary routes of exposureprimary routes of exposure
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Other routes of exposureOther routes of exposure
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Xenobiotics pass through severalXenobiotics pass through several
membranes of cellsmembranes of cells
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Absorption trough cellAbsorption trough cell
membranemembrane
 passive transferpassive transfer oror
• simple diffusion (or osmotic filtration)simple diffusion (or osmotic filtration)
• "passive" (filtration) - no cellular energy"passive" (filtration) - no cellular energy
or assistance requiredor assistance required
 facilitated transportfacilitated transport – needs energy– needs energy
• facilitated diffusionfacilitated diffusion
• active transportactive transport
• endocytosis (endocytosis (phagocytosisphagocytosis andand
pinocytosispinocytosis))
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Passive transferPassive transfer
 the most common phenomenonthe most common phenomenon
 Two factors determine the rate of transfer:Two factors determine the rate of transfer:
• difference indifference in concentrationsconcentrations of the substance onof the substance on
opposite sides of the membrane (osmotic pressure)opposite sides of the membrane (osmotic pressure)
• abilityability of the substanceof the substance to moveto move either through the smalleither through the small
pores in the membrane or the lipophilic interior of thepores in the membrane or the lipophilic interior of the
membranemembrane
 Properties of the chemical substance that affectProperties of the chemical substance that affect
its' ability for passive transfer are:its' ability for passive transfer are:
• lipid solubilitylipid solubility
• molecular sizemolecular size
• degree of ionizationdegree of ionization
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Illustration of passive diffusion andIllustration of passive diffusion and
filtration of xenobiotics through cellfiltration of xenobiotics through cell
membranemembrane
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Facilitated diffusionFacilitated diffusion
 As in simple diffusion, does not requireAs in simple diffusion, does not require
energy and follows a concentrationenergy and follows a concentration
gradient.gradient.
 The difference – involves a carrier-The difference – involves a carrier-
mediated transport mechanism.mediated transport mechanism.
• The results are similar to passive transport butThe results are similar to passive transport but
faster and capable of moving larger moleculesfaster and capable of moving larger molecules
that have difficulty diffusing through thethat have difficulty diffusing through the
membrane without a carrier.membrane without a carrier.
• Examples are the transport of sugar and aminoExamples are the transport of sugar and amino
acids into RBCs and the CNS.acids into RBCs and the CNS.
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sugar and amino acids transportion intosugar and amino acids transportion into
RBCs and CNSRBCs and CNS
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Active transportActive transport
 Substances movement through membraneSubstances movement through membrane
againstagainst the concentration gradient (from low tothe concentration gradient (from low to
higher concentrations).higher concentrations).
 substances aresubstances are
• unable to move by diffusion,unable to move by diffusion,
• unable to dissolve in the lipid layer, andunable to dissolve in the lipid layer, and
• too large to pass through the aqueous channels.too large to pass through the aqueous channels.
 Cellular energy from adenosine triphosphateCellular energy from adenosine triphosphate
(ATP) is required.(ATP) is required.
 important inimportant in
• the transport of xenobiotics into the liver, kidney, andthe transport of xenobiotics into the liver, kidney, and
central nervous system andcentral nervous system and
• for maintenance of electrolyte and nutrient balance.for maintenance of electrolyte and nutrient balance.
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Movement of NaMovement of Na++
& K& K++
against concentrationagainst concentration
gradient with the help of the ADP sodium-gradient with the help of the ADP sodium-
potassium pump.potassium pump.
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EndocytosisEndocytosis
 the cell surrounds the substance withthe cell surrounds the substance with
a section of its cell wall.a section of its cell wall.
 This engulfed substance and sectionThis engulfed substance and section
of membrane then separates fromof membrane then separates from
the membrane and moves into thethe membrane and moves into the
interior of the cell.interior of the cell.
 The two main forms of endocytosisThe two main forms of endocytosis
• phagocytosisphagocytosis
• pinocytosispinocytosis
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PhagocytosisPhagocytosis (cell eating)(cell eating)
 large particles suspended in thelarge particles suspended in the
extracellular fluid are engulfed andextracellular fluid are engulfed and
either transported into cells or areeither transported into cells or are
destroyed within the cell.destroyed within the cell.
 an important process for lungan important process for lung
phagocytes and certain liver andphagocytes and certain liver and
spleen cells.spleen cells.
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endocytosis membrane transportendocytosis membrane transport
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PinocytosisPinocytosis (cell drinking)(cell drinking)
 involves the engulfing of liquids orinvolves the engulfing of liquids or
very small particles that are invery small particles that are in
suspension within the extracellularsuspension within the extracellular
fluid.fluid.
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Absorption via GastrointestinalAbsorption via Gastrointestinal
(GI)Tract(GI)Tract
 Toxicants enter the body,Toxicants enter the body,
by passing through the GIby passing through the GI
mucosa, crossing severalmucosa, crossing several
membranes before enteringmembranes before entering
the blood stream.the blood stream.
 Absorption can occur at anyAbsorption can occur at any
place along the entire GI.place along the entire GI.
• degree of absorption isdegree of absorption is
 site-dependencesite-dependence
 GI content – foodGI content – food
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 Three main factors affect absorption at theThree main factors affect absorption at the
specific site :specific site :
1.1. type of cellstype of cells
2.2. period of time, the substance remainsperiod of time, the substance remains
3.3. pH of stomach or intestinal contentspH of stomach or intestinal contents
 MouthMouth && esophagus –esophagus – poor absorption sites forpoor absorption sites for
xenobiotics,xenobiotics,  very short residence timevery short residence time
 Stomach -Stomach - high acidityhigh acidity (pH 1-3),(pH 1-3),
• a significant site for absorption ofa significant site for absorption of weak organic acidsweak organic acids
- diffusible, nonionized and lipid-soluble form.- diffusible, nonionized and lipid-soluble form.
• weak basesweak bases , highly ionized - poorly absorbed., highly ionized - poorly absorbed.
• FoodFood interfere absorption – by >50%interfere absorption – by >50%
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 intestineintestine
• greatestgreatest
absorption, esp.absorption, esp.
the smallthe small
intestine.intestine.
• has a large surfacehas a large surface
area - facilitatesarea - facilitates
diffusion across thediffusion across the
cell membranescell membranes
 outward projectionsoutward projections
of thinof thin (one-cell(one-cell
thick)thick) mucosa intomucosa into
the lumenthe lumen (the(the
villi)villi)..
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• pH, near neutralpH, near neutral (pH 5-8)(pH 5-8),,
 weak bases and weak acids (nonionized form),weak bases and weak acids (nonionized form),
readily absorbed - passive diffusion.readily absorbed - passive diffusion.
 Lipid soluble, small molecules enter the body fromLipid soluble, small molecules enter the body from
intestine by passive diffusion.intestine by passive diffusion.
• passive diffusion, facilitated and activepassive diffusion, facilitated and active
transport mechanisms exist to movetransport mechanisms exist to move
 essential nutrients, - glucose, amino acids andessential nutrients, - glucose, amino acids and
calcium across the intestinal cells into the body.calcium across the intestinal cells into the body.
 Strong acids, strong bases, large molecules, andStrong acids, strong bases, large molecules, and
metals, including some important toxins, lead,metals, including some important toxins, lead,
thallium, and paraquatthallium, and paraquat (herbicide)(herbicide)
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• (+) slow movement, increases absorptivity(+) slow movement, increases absorptivity
• Intestinal microflora and gastrointestinalIntestinal microflora and gastrointestinal
enzymes affect the toxicity of ingestedenzymes affect the toxicity of ingested
substances.substances.
 biotransformed products may be absorbed and bebiotransformed products may be absorbed and be
more toxic than the ingested substance.more toxic than the ingested substance.
• example - formation of carcinogenic nitrosamines fromexample - formation of carcinogenic nitrosamines from
non-carcinogenic amines by intestinal flora.non-carcinogenic amines by intestinal flora.
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 coloncolon andand rectum –rectum –
• little absorption takes place, remains of thelittle absorption takes place, remains of the
stomach and small intestine.stomach and small intestine.
• some exceptions - medicines administered assome exceptions - medicines administered as
rectal suppositories with significantrectal suppositories with significant
absorption.absorption.
 AnusolAnusol (hydrocortisone preparation)(hydrocortisone preparation) used forused for
treatment of local inflammation which is partiallytreatment of local inflammation which is partially
absorbed (about 25%).absorbed (about 25%).
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Absorption via Respiratory TractAbsorption via Respiratory Tract
 Absorption can occur at any place within theAbsorption can occur at any place within the
upper respiratory tract.upper respiratory tract.
 three basic regions of absorption:three basic regions of absorption:
• nasopharyngeal regionnasopharyngeal region
• tracheobronchial regiontracheobronchial region
• pulmonary region.pulmonary region.
 the amount absorbed depend on physical formthe amount absorbed depend on physical form
and solubility of toxicants (and solubility of toxicants (gas/vapor or agas/vapor or a
particle)particle)..
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TheThe Respiratory TractRespiratory Tract
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 toxicity of inhaled materials depends on whethertoxicity of inhaled materials depends on whether
• the material is absorbed orthe material is absorbed or
• remains within the alveoli and small bronchioles.remains within the alveoli and small bronchioles.
 Non-absorbed foreign material can cause severeNon-absorbed foreign material can cause severe
toxic reactions within the respiratory system.toxic reactions within the respiratory system.
• chronic bronchitis,chronic bronchitis,
• alveolar breakdownalveolar breakdown (emphysema)(emphysema),,
• fibrotic lung disease,fibrotic lung disease,
• lung cancer.lung cancer.
• kill the alveolar macrophages, loss lung immunitykill the alveolar macrophages, loss lung immunity
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Absorption via Dermal RouteAbsorption via Dermal Route
 The skin consists ofThe skin consists of
three main layers ofthree main layers of
cells:cells:
• EpidermisEpidermis
• DermisDermis
• Subcutaneous tissueSubcutaneous tissue
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 The epidermisThe epidermis (and particularly the(and particularly the
stratum corneum)stratum corneum)
• regulating penetration of a skin contaminant.regulating penetration of a skin contaminant.
• consists of an outer layer of cells, packed withconsists of an outer layer of cells, packed with
keratin - the stratum corneum layer.keratin - the stratum corneum layer.
 devoid of blood vessels.devoid of blood vessels.
 The cell walls of the keratinized cells are double inThe cell walls of the keratinized cells are double in
thickness due to the presence of the keratin,thickness due to the presence of the keratin,
• chemically resistant and an impenetrable material.chemically resistant and an impenetrable material.
• resistant to penetration by chemicals.resistant to penetration by chemicals.
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 Toxicants move across the stratum corneum byToxicants move across the stratum corneum by
passive diffusion.passive diffusion.
• no active transportno active transport
• Polar compoundsPolar compounds (which are water-soluble)(which are water-soluble) - diffusediffuse
through the outer surface of the hydrated keratinizedthrough the outer surface of the hydrated keratinized
layer.layer.
• Nonpolar compoundsNonpolar compounds (which are lipid soluble)(which are lipid soluble) diffusediffuse
through the lipid material between the keratin filaments.through the lipid material between the keratin filaments.
 May absorbed through the sweat glands,May absorbed through the sweat glands,
sebaceous glands, and hair follicles.sebaceous glands, and hair follicles.
 the dermis, and subcutaneous tissue layers arethe dermis, and subcutaneous tissue layers are
far less resistant to further diffusion.far less resistant to further diffusion.
• They contain a porous, nonselective aqueous diffusionThey contain a porous, nonselective aqueous diffusion
medium,medium,
• can be penetrated by simple diffusion & reach the bloodcan be penetrated by simple diffusion & reach the blood
vessles.vessles.
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Other Routes of Exposure - InjectionOther Routes of Exposure - Injection
 Parenteral routesParenteral routes, - injection into the body, via, - injection into the body, via
syringe and hollow needle.syringe and hollow needle.
 Intradermal injections -Intradermal injections - direct into the skin, justdirect into the skin, just
under the stratum corneum.under the stratum corneum.
• subcutaneous injectionsubcutaneous injection - beneath the skin,- beneath the skin,
• intramuscular routeintramuscular route - direct into muscle tissue,- direct into muscle tissue,
pharmaceuticals: antibiotics and vaccinespharmaceuticals: antibiotics and vaccines
• intravenousintravenous oror intraarterial routesintraarterial routes - direct into large blood- direct into large blood
vessels. Sepcific purpose - irritating or immediate action, eg.vessels. Sepcific purpose - irritating or immediate action, eg.
anesthesia.anesthesia.
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• intraperitoneal injectionintraperitoneal injection - Injection into the abdominal cavity.- Injection into the abdominal cavity.
• intrapleural injection -intrapleural injection - directly into the chest cavity,directly into the chest cavity,
 ImplantationImplantation ––
• used to allow slow, time-release of a substanceused to allow slow, time-release of a substance (e.g.,(e.g.,
hormones).hormones).
• In other cases, no absorption is desired, such as for implantedIn other cases, no absorption is desired, such as for implanted
medical devices and materialsmedical devices and materials (e.g., artificial lens, tendons and(e.g., artificial lens, tendons and
joints, and cosmetic reconstruction).joints, and cosmetic reconstruction).
 Skin penetrationSkin penetration
• as the result of accidents or violence (weapons, etc.).as the result of accidents or violence (weapons, etc.).
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 Conjunctival instillationsConjunctival instillations (eye drops)(eye drops)
• are used for treatment of ocular conditions where highare used for treatment of ocular conditions where high
concentrations are needed on the outer surface of the eye,concentrations are needed on the outer surface of the eye,
not possible by other routesnot possible by other routes
 SuppositorySuppository ––
• a substance be deposited in body openings where higha substance be deposited in body openings where high
concentrations and slow release may be needed whileconcentrations and slow release may be needed while
keeping systemic absorption to a minimum.keeping systemic absorption to a minimum.
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DistributionDistribution
 the process whereby an absorbed chemicalthe process whereby an absorbed chemical
moves away from the site of absorption to othermoves away from the site of absorption to other
areas of the body.areas of the body.
 The questions:The questions:
• How do chemicals move through the body?How do chemicals move through the body?
• Does distribution vary with the route of exposure?Does distribution vary with the route of exposure?
• Is a chemical distributed evenly to all organs orIs a chemical distributed evenly to all organs or
tissues?tissues?
• How fast is a chemical distributed?How fast is a chemical distributed?
• Why do some chemicals stay in the body for a longWhy do some chemicals stay in the body for a long
time whereas others are eliminated quickly?time whereas others are eliminated quickly?
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 A toxicant can leave the interstitial fluid by entering :A toxicant can leave the interstitial fluid by entering :
• local tissue cells –local tissue cells – almost staticalmost static
• blood capillaries and the blood circulatory system –blood capillaries and the blood circulatory system – fastfast
movingmoving
• the lymphatic system –the lymphatic system – slow movingslow moving
 The distribution of a xenobiotic is greatly affected byThe distribution of a xenobiotic is greatly affected by
whether it binds to plasma protein.whether it binds to plasma protein.
• bind to these plasma proteinsbind to these plasma proteins (especially albumin),(especially albumin), "removes""removes"
the toxicant from potential cell interaction.the toxicant from potential cell interaction.
• only the free substance is available to pass through theonly the free substance is available to pass through the
capillary membranes.capillary membranes.
• Protein-binding in the plasma greatly affects distribution,Protein-binding in the plasma greatly affects distribution,
 prolongs the half-life within the body, andprolongs the half-life within the body, and
 affects the dose threshold for toxicity.affects the dose threshold for toxicity.
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 Once a chemical is in the blood stream it may be:Once a chemical is in the blood stream it may be:
• excretedexcreted
• storedstored
• biotransformed into different chemicalsbiotransformed into different chemicals (metabolites)(metabolites)
• its metabolites may be excreted or storedits metabolites may be excreted or stored
• the chemical or its metabolites may interact or bind withthe chemical or its metabolites may interact or bind with
cellular componentscellular components
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Influence of Route of ExposureInfluence of Route of Exposure
 TheThe route of exposureroute of exposure ––
1.1. ToxicantToxicantGI tract, lung or skinGI tract, lung or skin  ToxicantToxicant (or(or
its' metabolites)its' metabolites)  blood or lymphblood or lymph  liverliver
(BIOTRANSFORMED)(BIOTRANSFORMED) Target SitesTarget Sites
== "first pass effect.""first pass effect."
OrOr
2. Toxicant2. ToxicantGI tract, lung or skinGI tract, lung or skin  ToxicantToxicant (or(or
its' metabolites)its' metabolites)  blood or lymph (MINIMUMblood or lymph (MINIMUM
BIOTRANSFORMED)BIOTRANSFORMED)  Target Sites.Target Sites.
important factor that can affect theimportant factor that can affect the
concentration of the toxicant at Target Sites.concentration of the toxicant at Target Sites.
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Structural Barriers to DistributionStructural Barriers to Distribution
 Quantity of toxicants received by TargetQuantity of toxicants received by Target
Sites determined bySites determined by
• volume of bloodvolume of blood flowing through the sitesflowing through the sites
• presence of specialpresence of special "barriers""barriers" to slow downto slow down
toxicant entrance.toxicant entrance.
 LiverLiver (28%),(28%), kidneyskidneys (23%),(23%), heartheart
muscle, and brain receive a largemuscle, and brain receive a large
percentage of the total cardiac output.percentage of the total cardiac output.
• Bone and adipose tissues - storage sites (lowBone and adipose tissues - storage sites (low
blood flow in) receive less toxicants.blood flow in) receive less toxicants.
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 Tissue affinityTissue affinity determines the degree ofdetermines the degree of
concentration of a toxicant.concentration of a toxicant.
• adipose tissue (less blood flow), concentratesadipose tissue (less blood flow), concentrates
lipid-soluble toxicants.lipid-soluble toxicants.
 Structural barriersStructural barriers exist that restrictexist that restrict
entrance of toxicants into certain organsentrance of toxicants into certain organs
or tissues.or tissues.
• Primary barriers - brain, placenta, and testes.Primary barriers - brain, placenta, and testes.
 Blood-brain barrierBlood-brain barrier protects the brain from mostprotects the brain from most
toxicants.toxicants.
 Placental barrierPlacental barrier protects the developing andprotects the developing and
sensitive fetus from most toxicants distributed in thesensitive fetus from most toxicants distributed in the
maternal circulation.maternal circulation.
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Storage Sites
 The primary storage sitesThe primary storage sites
• adipose tissue, bone, liver and kidneys.adipose tissue, bone, liver and kidneys.
 Adipose tissuesAdipose tissues..
• Lipid-soluble toxicantsLipid-soluble toxicants
 deposited along with triglyceridesdeposited along with triglycerides
 continual exchange with blood (to remobilized into thecontinual exchange with blood (to remobilized into the
blood for further distribution and elimination, orblood for further distribution and elimination, or
redeposited in other adipose tissue cells.redeposited in other adipose tissue cells.
 Bone.Bone.
• proteins and the mineral salt hydroxyapatite.proteins and the mineral salt hydroxyapatite.
• contains a sparse blood supply but is a live organ.contains a sparse blood supply but is a live organ.
• form bone, calcium and hydroxyl ions are incorporatedform bone, calcium and hydroxyl ions are incorporated
into the hydroxyapatite-calcium matrix.into the hydroxyapatite-calcium matrix.
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• Other minerals subtitution: strontiumOther minerals subtitution: strontium (Sr)(Sr) or leador lead (Pb)(Pb)
for calciumfor calcium (Ca),(Ca), fluoridefluoride (F(F--
)) for hydroxylfor hydroxyl (OH(OH--
)) ionsions..
• toxicants stored in the matrix will slowly be released totoxicants stored in the matrix will slowly be released to
reenter the circulatory system.reenter the circulatory system.
 LiverLiver
• a storage site for some toxicants.a storage site for some toxicants.
• large blood flowlarge blood flow
• hepatocyteshepatocytes (i.e., liver cells)(i.e., liver cells) contain proteins that bindcontain proteins that bind
to some chemicals, including toxicants.to some chemicals, including toxicants.
 KidneysKidneys
• have a high blood flow, exposes these organs tohave a high blood flow, exposes these organs to
toxicants in high concentrationstoxicants in high concentrations
• Storage - associated primarily with the cells of theStorage - associated primarily with the cells of the
nephronnephron (the functional unit for urine formation).(the functional unit for urine formation).
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Toxicity of Target SitesToxicity of Target Sites
(or Organs)(or Organs)
 Blood -Blood - Hemotoxicity.Hemotoxicity.
 Liver - Hepatotoxicity.Liver - Hepatotoxicity.
 Kidney - Nephrotoxicity.Kidney - Nephrotoxicity.
 Brain/Nerves - Neurotoxicity.Brain/Nerves - Neurotoxicity.
 Skin - Dermotoxicity.Skin - Dermotoxicity.
 Lung - PulmonotoxicityLung - Pulmonotoxicity
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Biotransformation of XenobioticsBiotransformation of Xenobiotics
 Biological basis for xenobiotic
metabolism:
• To convert lipid-soluble, non-polar, non-
excretable forms of chemicals to water-
soluble, polar forms that are excretable
in bile and urine
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MetabolismMetabolism
 Sum of biochemical rxns occurring to a moleculeSum of biochemical rxns occurring to a molecule
within the body.within the body.
• Anabolism - “build-up”Anabolism - “build-up”
• Catabolism - “break-down”Catabolism - “break-down”
 Occurs in the cytoplasm or at specific organellesOccurs in the cytoplasm or at specific organelles
within the cell.within the cell.
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Biotransformation ReactionsBiotransformation Reactions
 Phase I Reactions
• Enzymatic reactions that add or expose
functional groups to xenobiotics such as -OH,
-SH, -NH2 or –COOH
• Functional groups are analogous to having a
trailer hitch on a vehicle
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Biotransformation Reactions
 Phase II Reactions
• Enzymatic reactions that result in the
conjugation of large water-soluble, charged
(polar) biomolecules to xenobiotics
• For these reactions to occur, a functional
group must be present on either the parent
compound or its Phase I product
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MKA2009© 5555
Major Categories/ReactionsMajor Categories/Reactions
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MKA2009© 5656
The Truck-Hitch-Trailer Analogy toThe Truck-Hitch-Trailer Analogy to
Xenobiotic BiotransformationXenobiotic Biotransformation
Foreign Chemical
(xenobiotic)
TRUCK
• lipophilic
• not charged
• not water soluble
• poorly excretable
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MKA2009© 5757
Phase 1 enzymes
add or expose a
functional group
HITCH
• still lipophilic
• possibly reactive
• poorly water soluble
• catalyzed by P450s
Foreign Chemical
(xenobiotic)
TRUCK
• lipophilic
• not charged
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MKA2009© 5858
Phase 2 enzymes
conjugate (transfer)
endogenous molecules*
to the functional group
Phase 1 enzymes
add or expose a
functional group
HITCH
• still lipophilic
• possibly reactive
• poorly water soluble
• catalyzed by P450s
Foreign Chemical
(xenobiotic)
TRUCK
• lipophilic
• not charged
• not lipophilic
• usually not reactive
• water soluble products
• excretable
• catalyzed by
transferases
TRAILER
* sugars, amino acids, sulfates, acetyl groups
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MKA2009© 5959
Biotransformation Reactions:Phase I
Exposing a Functional Group on
the Starting Compound
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MKA2009© 6161
Enzymes of BiotransformationEnzymes of Biotransformation
Phase I EnzymesPhase I Enzymes
 Oxidation (most important).Oxidation (most important).
• Add O, remove H, increase valence.Add O, remove H, increase valence.
• Cytochrome P-450, alcohol dehydrogenase,Cytochrome P-450, alcohol dehydrogenase,
oxidases, others.oxidases, others.
 Reduction (less important).Reduction (less important).
• Remove O, add H, decrease valence.Remove O, add H, decrease valence.
• Reductases.Reductases.
 Hydrolysis.Hydrolysis.
• Add water.Add water.
• Esterases, phosphatases, others.Esterases, phosphatases, others.
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MKA2009© 6363
Enzymes of Biotransformation, 2Enzymes of Biotransformation, 2
Phase II EnzymesPhase II Enzymes
 Conjugation reactions.Conjugation reactions.
 Enzymes (tranferases) + cofactor.Enzymes (tranferases) + cofactor.
• Enzyme catalyzes.Enzyme catalyzes.
• Cofactor donates group.Cofactor donates group.
 Glucuronic acid, glutathione, sulfate, acetyl group,Glucuronic acid, glutathione, sulfate, acetyl group,
methyl group.methyl group.
 Tends to increase molecular size and polarityTends to increase molecular size and polarity
for excretion.for excretion.
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MKA2009© 7272
BiotransformationBiotransformation
 serves as a defense mechanismserves as a defense mechanism
• toxic xenobiotics and body wastestoxic xenobiotics and body wastes  harmful,harmful,
excretable substances (esp. lipophilic subst)excretable substances (esp. lipophilic subst)
 Eg. Important biotransformation ofEg. Important biotransformation of
“bilirubin”“bilirubin”
• Bilirubin = toxic to the brain of newborns, ifBilirubin = toxic to the brain of newborns, if
present in high concentrations,present in high concentrations,  irreversibleirreversible
brain injury.brain injury.
• In normal liver: RBCIn normal liver: RBC  haemoglobinhaemoglobin 
lipophilic bilirubinlipophilic bilirubin  hydrophilic metaboliteshydrophilic metabolites
 bilebile  excreation (feces)excreation (feces)
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MKA2009© 7373
 detoxificationdetoxification - biotransformation results in- biotransformation results in
metabolites of lower toxicity.metabolites of lower toxicity.
 bioactivationbioactivation - the metabolites are more toxic- the metabolites are more toxic
than the parent substance.than the parent substance.
• reactive metabolite may interact with cellularreactive metabolite may interact with cellular
macromolecules (e.g., DNA).macromolecules (e.g., DNA).
 serious health effect, eg., cancer or birth defects.serious health effect, eg., cancer or birth defects.
 biotransformation of vinyl chloride to vinyl chloridebiotransformation of vinyl chloride to vinyl chloride
epoxide,epoxide,  covalently binds to DNA and RNA, a stepcovalently binds to DNA and RNA, a step
leading to cancer of the liver.leading to cancer of the liver.
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MKA2009© 7474
ExcretionExcretion
 excretion (elimination) – a processexcretion (elimination) – a process
whereby a substance leaves thewhereby a substance leaves the
body.body.
 Toxicants or their metabolitesToxicants or their metabolites
eliminated by several routes.eliminated by several routes.
• The main routes of excretion are viaThe main routes of excretion are via
urine, feces, and exhaled air.urine, feces, and exhaled air.
 organ systems involved - urinary system,organ systems involved - urinary system,
gastrointestinal system and respiratorygastrointestinal system and respiratory
system.system.
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MKA2009© 7575
Urinary ExcretionUrinary Excretion
 Elimination of substances by theElimination of substances by the
kidneys into the urinekidneys into the urine
 The functional unit of the kidney -The functional unit of the kidney -
nephron.nephron.
• has three primary regions,has three primary regions,
 the glomerulus,the glomerulus,
 proximal tubule,proximal tubule,
 the distal tubule.the distal tubule.
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MKA2009© 7878
 Three processes in urinary excretion: filtration,Three processes in urinary excretion: filtration,
secretion, and reabsorption.secretion, and reabsorption.
 FiltrationFiltration, the first process, in the glomerulus,, the first process, in the glomerulus,
 SecretionSecretion, in the proximal tubule, transporting, in the proximal tubule, transporting
certain molecules out of the blood and into thecertain molecules out of the blood and into the
urine.urine.
 Reabsorption,Reabsorption, mainly in the proximal convolutedmainly in the proximal convoluted
tubule,tubule,
• passive transfer – moving from a high concentration inpassive transfer – moving from a high concentration in
the proximal tubule to the lower concentration in thethe proximal tubule to the lower concentration in the
capillaries surrounding the tubule.capillaries surrounding the tubule.
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MKA2009© 7979
 Kidneys, damaged by toxinsKidneys, damaged by toxins
(nephrotoxicity), infectious diseases, or as(nephrotoxicity), infectious diseases, or as
a consequence of age, - unable toa consequence of age, - unable to
eliminate toxicants.eliminate toxicants.
 The presence ofThe presence of albuminalbumin in the urinein the urine
indicates that the glomerulus filteringindicates that the glomerulus filtering
system is damaged letting large moleculessystem is damaged letting large molecules
pass through.pass through.
 The presence ofThe presence of glucoseglucose in the urine is anin the urine is an
indication that tubular reabsorption hasindication that tubular reabsorption has
been impaired.been impaired.
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MKA2009© 8080
Fecal ExcretionFecal Excretion
 occurs via two processes,occurs via two processes,
• excretion in bileexcretion in bile
• direct excretion into the lumen of thedirect excretion into the lumen of the
gastrointestinal tractgastrointestinal tract
 biliary routebiliary route ––
• important mechanism.important mechanism.
• involves active secretion rather than passiveinvolves active secretion rather than passive
diffusion.diffusion.
• substances to be excreted - large, ionizedsubstances to be excreted - large, ionized
molecules, molecular weightmolecules, molecular weight (greater than(greater than
300)300) conjugates.conjugates.
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MKA2009© 8282
• enterohepatic circulationenterohepatic circulation - excretionexcretion
ofof toxicantstoxicants into theinto the intestinal tractintestinal tract viavia
thethe bilebile and reabsorption and return toand reabsorption and return to
the liver by the portal circulation.the liver by the portal circulation.
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MKA2009© 8383
 directdirect intestinal excretionintestinal excretion
• not a major route of elimination,not a major route of elimination,
• Some substances, - poorly ionized in plasmaSome substances, - poorly ionized in plasma
(such as weak bases),(such as weak bases), passively diffusepassively diffuse
through the walls of the capillaries, throughthrough the walls of the capillaries, through
the intestinal submucosa, and into thethe intestinal submucosa, and into the
intestinal lumen.intestinal lumen.
• slow process - important elimination route onlyslow process - important elimination route only
for those xenobiotics that have slowfor those xenobiotics that have slow
biotransformation, or slow urinary or biliarybiotransformation, or slow urinary or biliary
excretion.excretion.
• Increasing lipid content of the intestinal tractIncreasing lipid content of the intestinal tract
can enhance intestinal excretion of somecan enhance intestinal excretion of some
lipophilic substances.lipophilic substances.
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MKA2009© 8484
Exhaled AirExhaled Air
 lungs - important route of excretion for gaseouslungs - important route of excretion for gaseous
xenobioticsxenobiotics (and metabolites)(and metabolites) in the blood.in the blood.
 passive diffusion from the blood into the alveolus,passive diffusion from the blood into the alveolus,
 Gases with a low solubility in blood rapidlyGases with a low solubility in blood rapidly
eliminated than those gases with a higheliminated than those gases with a high
solubility.solubility.
 Volatile liquids dissolved in the blood excreted viaVolatile liquids dissolved in the blood excreted via
the expired air.the expired air.
 The amount of a liquid excreted by the lungs isThe amount of a liquid excreted by the lungs is
proportional to its vapor pressure.proportional to its vapor pressure.
 Exhalation can be a very efficient route ofExhalation can be a very efficient route of
excretion for lipid soluble substances.excretion for lipid soluble substances.
• due to the very close proximity of capillary and alveolardue to the very close proximity of capillary and alveolar
membranes.membranes.
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MKA2009© 8585
Other Routes of ExcretionOther Routes of Excretion
 via mother's milk, sweat, saliva,via mother's milk, sweat, saliva,
tears, and semen.tears, and semen.
 all other body secretions orall other body secretions or
tissuestissues (including the saliva, sweat,(including the saliva, sweat,
tears, hair, and skin)tears, hair, and skin) - minor- minor
importance.importance.
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Absorption, distribution, metabolism & elimination

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