1. HLTH 340 Lecture A4 Toxicokinetic processes: Distribution (part-1)
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2. Distribution kinetics
distribution is second phase of toxicokinetic ADME processes
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
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

3. First-pass effect by the liver
filtered blood to systemic circulation
xenobiotics in food and water carried from gut to liver via hepatic portal vein
xenobiotics circulating in systemic blood are carried to liver via hepatic artery
liver filters out a fraction of lipophiles into hepatocytes
remaining lipophiles enter the systemic circulation via hepatic vein
hepatocytes secrete their intracellular lipophiles to bile
biliary excretion carries lipophiles to gut --> feces
lipophiles
systemic blood to liver
bile to GI tract
blood from GI tract

4. Blood Partitioning: binding of xenobiotics to plasma proteins and erythrocytes
bound toxicant
(erythrocytes)
xenobiotics are carried dissolved in blood plasma in 2 phases
free plasma phase -- molecules dissolved as free solute in water
protein bound phase – molecules reversibly (loosely) bound to large plasma proteins
hydrophiles readily dissolve in water phase of blood plasma
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
carried mainly in protein bound phase
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)

5. Free-plasma and erythrocyte-bound xenobiotics example: lead binding to ALAD protein
plasma Pb++
erythrocyte Pb++
blood
Pb++

6. Free-plasma and erythrocyte-bound xenobiotics example: lead binding to ALAD protein
CNS (brain)
spongy
bone
kidney
CNS (brain)
spongy
bone
kidney
higher
neurotoxicity
lower
neurotoxicity
higher
renal toxicity
avg plasma Pb++
lower plasma Pb++
avg erythrocyte Pb++
higher erythrocyte Pb++
average
blood
Pb++
elevated
blood
Pb++ - -
ALAD-1 polymorphism
ALAD-2 polymorphism

7. Tissue distribution and bioavailability influences the ‘ ‘target tissue’ and the ‘critical effect’
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)
critical effect
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
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

8. Perfusion-limited and partition-limited tissue distribution
perfusion-limited tissue distribution
tissue perfusion rate defines rate of blood flow to organs
highly perfused tissues (often more vulnerable)
liver, kidneys, lung, brain
poorly perfused tissues (often less vulnerable)
skin, fat, connective tissues, bone, muscle (variable)
partition-limited tissue distribution
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
also may be affected by carrier-mediated transport of ionic or polar xenobiotics
using selective membrane channels or pumps
e.g. lead: can be transported into tissues using the calcium or iron transporter channels
also may be affected by liver metabolism of a xenobiotic to its metabolite(s)
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

9. PBPK computer model simulating the ADME toxicokinetics of an inhaled xenobiotic (e.g. chloroform)
chloroform (IN)
chloroform (OUT)
Kp tissue/blood
partition defines distribution
Kp tissue/blood
arterial blood IN
venous blood
OUT
perfusion defines distribution
Kp tissue/blood
Q = tissue perfusion rate
metabolism defines distribution
C = blood concentration