Toxicokinetics

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Toxicokinetics

• Dr. Jena Hamra

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Toxokinetics

• Mathematical description or model that relates
  the plasma concentration of a chemical to the
  rates of drug disposition
• Absorption
• Distribution
• Biotransformation
• Elimination

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Distribution

• Movement of chemical to organs or tissues from
  the circulation
• Occurs simultaneously with absorption
• Three primary compartments
• Plasma water
• Extracellular water
• Intracellular water

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Toxicokinetics

• Two models
• Classic model
• Compartmental
• Simplest
• Physiological (PBPK)
• Compartments based on specific organs or tissues
• Based on physiological parameters
• Can predict tissue concentrations

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Classic Toxicokinetics

• Compartmental
• Central compartment
• Plasma
• Tissues with high blood flow
• Rapid equilibration
• Peripheral compartments
• Tissues that equilibrate more slowly
• Equilibrate at different rates

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One Compartment Models

• Simplest
• Assume chemical does not leave the central
  compartment
• Changes in plasma concentrations reflect
  proportional changes in tissue chemical
  concentrations
• Semi-logarithmic graph of time course yields a
  straight line

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Multi-Compartment Models

• Drugs absorbed into central compartment and
  distributed to peripheral compartments
• Elimination from central compartment
• Semi-logarithmic graph of time course data does
  NOT yield a straight line

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Volume of Distribution (Vd)

• Apparent space or volume that a chemical is
  distributed into in the body
• Higher the Vd, the greater the movement into all
  the tissues in the body
• Units Liters or Liters/Kg
• One compartment model
• Vd DoseIV/ C0
• C0 Plasma drug concentration immediately
  following distribution

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Clearance

• Rate of elimination of a chemical from the body
• Units Milliliters/minute
• Total body clearance
• Sum of clearances from all eliminating organs
• One compartment model
• Cl Vd X kel
• Two compartment model
• Cl Vd X ?

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First and Zero Order Kinetics

• First order kinetics
• Rate of elimination of chemical is proportional
  to the concentration of the chemical in the body
• Elimination constant, Vd, Cl and half-life are
  independent of dose
• Zero order kinetics
• Rate of elimination is constant
• Independent of concentration of chemical in body

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Elimination Half-life

• Time required to eliminate half of the amount of
  a chemical in the body
• Reduce plasma concentration by 50
• T1/2 0.693Vd/Cl 0.693/Ke
• ? Vd ? ? T1/2

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Bioavailability

• Fraction of a dose (oral) that reaches the
  systemic circulation

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Physiologic Toxicokinetics

• Compartments based on organs and tissues
• No generic model
• Each compartment is a tissue or region of the
  body with a UNIFORM concentration of the
  xenobiotic
• Subcompartments
• Vascular
• Interstitial
• Intracellular

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Parameters

• Anatomic
• Size/volumes
• Physiologic
• Blood flow
• Cardiac output
• Ventilation
• Thermodynamic
• Distribution
• Transport

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Perfusion Limited Compartments

• Flow limited
• Cell membrane permeability is much greater than
  the blood flow rate to the tissue
• Most tissues
• Concentration in plasma is in equilibrium with
  concentration in interstitial space
• Extracellular space

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Diffusion Limited Compartments

• Transport of chemical across membrane is much
  slower than the blood flow to the tissue

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Specialized Compartments

• Lung
• Assumptions
• Ventilation continuous
• No absorption in conducting airways
• Flow-limited diffusion
• No storage of chemical in lung
• Alveolar/blood in rapid equilibrium
• Liver
• Saturable kinetics!

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