HLTH 340
Lecture A4
Toxicokinetic processes:
Distribution (part-1)
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Distribution kinetics
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distribution is second phase of toxicokinetic ADME processes
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describes processes that determine where in the body a xenobiotic will go after absorption
disposition = distribution + metabolism
clearance = metabolism + excretion
factors affecting the distribution kinetics of a xenobiotic
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anatomical structure of blood circulation at site of absorption (first-pass effect)
partitioning of xenobiotic transport between blood components
patterns of blood flow after absorption (perfusion kinetics)
blood-tissue partitioning (tissue bioavailability)
internal membrane barriers
tissue sequestration mechanisms (depots and sinks)
depot mobilization mechanisms
effect of metabolic biotransformation reactions
ionic trapping and redox trapping of xenobiotics (or their metabolites) in a tissue
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First-pass effect by the liver
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xenobiotics in food and water
carried from gut to liver via
hepatic portal vein
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xenobiotics circulating in
systemic blood are carried to
liver via hepatic artery
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liver filters out a fraction of
lipophiles into hepatocytes
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filtered blood to systemic circulation
lipophiles
remaining lipophiles enter the
systemic circulation via hepatic
vein
systemic blood to liver
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hepatocytes secrete their
intracellular lipophiles to bile
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biliary excretion carries lipophiles
to gut --> feces
bile to GI tract
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HLTH 340 Lecture A4
blood from GI tract
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Blood Partitioning: binding of xenobiotics to
plasma proteins and erythrocytes
bound toxicant
(erythrocytes)
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xenobiotics are carried dissolved in blood plasma in 2 phases
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hydrophiles readily dissolve in water phase of blood plasma
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carried mainly in protein bound phase
plasma proteins
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carried mainly in free plasma phase
exception: most metal ions are carried by specific metal ion transporter proteins
lipophiles tend to bind to plasma protein phase of blood plasma
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free plasma phase -- molecules dissolved as free solute in water
protein bound phase – molecules reversibly (loosely) bound to large plasma proteins
albumin (most common) -- prefers neutral lipophilic and mildly acidic xenobiotics (about 50 sites per protein)
various types of lipoproteins -- prefers strongly lipophilic molecules
special carrier proteins (e.g. transferrin for iron and some other metal ions)
erythrocytes (RBCs) can selectively bind certain metal ions (e.g.iron, zinc, lead)
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Free-plasma and erythrocyte-bound xenobiotics
example: lead binding to ALAD protein
plasma Pb++
erythrocyte Pb++
blood
Pb++
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Free-plasma and erythrocyte-bound xenobiotics
example: lead binding to ALAD protein
CNS (brain)
spongy
bone
kidney
higher
neurotoxicity
CNS (brain)
lower
neurotoxicity
avg plasma Pb++
higher
renal toxicity
higher erythrocyte Pb++
elevated
blood
Pb++
average
blood
Pb++
kidney
lower plasma Pb++
avg erythrocyte Pb++
ALAD-1 polymorphism
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spongy
bone
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ALAD-2 polymorphism
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Tissue distribution and bioavailability influences the
‘ ‘target tissue’ and the ‘critical effect’
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target tissue
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xenobiotics often produce their primary toxic effects on specific tissues or organs
toxic effect is possible only when a xenobiotic is able to be absorbed from the site of entry into the blood
and then is distributed preferentially from the blood to the specific target tissue (where it is harmful)
bioavailability
extent of (1) absorption and (2) distribution of a xenobiotic to the target tissue
(expressed as a fraction or % of the total dose)
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critical effect
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bioavailability
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defined as the toxic effect observed in an essential physiological process at the lowest administered dose
percentage of xenobiotic undergoing absorption from GI tract to blood (oral bioavailability)
fraction of xenobiotic freely dissolved in blood plasma (effective blood concentration)
degree of permeation of xenobiotic from blood into a specific tissue (tissue/blood partition)
xenobiotic uptake at the target tissue is affected by several types of distribution factors
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tissue perfusion rate by arterial blood supply
tissue/blood partition coefficient Kp (tissue/blood)
internal membrane barriers (e.g. BBB)
sequestration in non-target issues
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Perfusion-limited and
partition-limited tissue distribution
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perfusion-limited tissue distribution
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tissue perfusion rate defines rate of blood flow to organs
highly perfused tissues (often more vulnerable)
liver, kidneys, lung, brain
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poorly perfused tissues (often less vulnerable)
skin, fat, connective tissues, bone, muscle (variable)
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partition-limited tissue distribution
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xenobiotics partition differentially between high-fat and low-fat content in tissues
mainly determined by Kow partition coefficient (lipophilic vs hydrophilic)
• high fat tissues -- adipose tissue (fat), brain, lungs, reproductive organs
• low fat tissues -- heart, kidney, muscles, connective tissue
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also may be affected by carrier-mediated transport of ionic or polar xenobiotics
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using selective membrane channels or pumps
e.g. lead: can be transported into tissues using the calcium or iron transporter channels
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also may be affected by liver metabolism of a xenobiotic to its metabolite(s)
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e.g. bisphenol A (BPA) is lipophilic --> binds to plasma proteins (albumin) --> persists in body
bisphenol A glucuronide metabolite (BPA-gluc) is hydrophilic --> rapidly excreted by kidneys
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PBPK computer model simulating the ADME toxicokinetics
of an inhaled xenobiotic (e.g. chloroform)
chloroform (IN)
chloroform (OUT)
Kp tissue/blood
partition defines distribution
arterial blood
IN
Kp tissue/blood
venous blood
OUT
perfusion defines distribution
Kp tissue/blood
Q = tissue perfusion rate
metabolism defines distribution
C = blood concentration
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