Toxicokinetics

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Toxicokinetics
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Toxicokinetics

• Is the study of the modeling and mathematical
  description of the time course of disposition of
  xenobiotics in the whole organism.

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Toxicokinetics

• Classic toxicokinetics
• Physiologic toxicokinetics

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Classic toxicokinetics

• One compartment model
• Two compartment model
• Elimination
• Apparent Volume of Distribution
• Clearance
• Half-life
• Saturation toxicokinetics
• Bioavailability

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Elimination

• Biotransformation
• Excretion
• Exhalation
• Usually as first order process(one compartment)
  the rate of elimination at any time is
  proportional to the amount of the chemical in the
  body at that time (below saturation level for
  elimination)

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Apparent Volume of Distribution

• Is the apparent space into which an amount of
  chemical is distributed in the body to result in
  a given plasma concentration

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V(d) Dose(iv)/B x AUC)

• B elimination rate constant
• AUC is the area under the curve of
  concentration verse time

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Clearance

• Clearance describes the rate of chemical
  elimination from the body in terms of the volume
  of fluid containing chemical that is cleared per
  unit of time.

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Half-life

• The half-life of elimination (T1/2) is the time
  required for the blood or plasma chemical
  concentration to decrease by one-half and is
  dependent on both volume of distribution and
  clearance.

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• T1/2 (0.693 x Vd)/Cl

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Saturation toxicokinetics

• May affect the volume of distribution or the rate
  of elimination

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Processes that may be saturated

• Biotransformation
• Active transport
• Protein binding

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Zero order verse first order kinetics

• Rate or amount of chemical eliminated at any time
  is independent of the amount of chemical in the
  body
• For zero order processes, the arithmetic plot of
  plasma conc. Versus time yields a straight line
• A true t(1/2) or k(el) does not exist but differs
  depending on the dose

• For first order elimination, the rate at which a
  chemical is eliminated at any time is directly
  proportional to the amount of that chemical in
  the body at that time
• A semilog plot of plasma conc. Versus time yields
  a straight line
• Elimination rate constant (B or k(el), V(d), Cl,
  T(1/2) are independent of dose
• Concentration of chemical in plasma and other
  tissues decreases similarly by some constant
  fraction per unit of time, the elimination rate
  constant, B or k(el)

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Bioavailability

• Is the fraction of the dose that is absorbed
  systemically

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Physiologic toxicokinetics

• Basic Model Structure
• Compartments
• Parameters
• Perfusions-limited compartments
• Diffusion limited compartments
• Specialized compartments

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Advantages of physiologically based models

• Models can provide the time course of
  distribution of xenobiotics to any organ or
  tissue
• They allow estimation of the effects of changing
  physiologic parameters on tissue concentrations
• The same model can predict the toxicokinetics or
  chemicals across species by means of allometric
  scaling
• Complex dose regimens and saturable processes
  such as metabolism and binding are accommodated
  easily

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Basic model structure
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Compartments
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Parameters

• Anatomic
• Physiologic
• Thermodynamic
• Transport

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Anatomic

• Describes the compartments physically
• Size of compartment
• Specified as a volume (ml or l)
• Data for specific organs known in literature

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Physiologic

• Includes processes such as
• Blood flow (volume/time) to specific compartments
• Ventilation rate for inhalation and exhalation
  (elimination) routes
• Renal clearance rates and parameters to describe
  biotransformation are needed

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Thermodynamic

• Involves the relationship between total
  concentration of xenobiotic in tissue and the
  free concentration within the tissue
• Assumes equilibrium between total and free
  xenobiotic
• Only free is available for binding, metabolism or
  removal from the tissue by blood
• Need to know partition or distribution
  coefficients for calculations

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Transport

• Refers to the movement across a biologic membrane
  
• Passive diffusion
• Carrier-mediated transport
• Facilitated transport
• Flux is the rate of transfer of a xenobiotic
  across a boundary
• Permeability coefficient

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Perfusion limited compartment
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Diffusion-limited compartments
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Specialized compartments
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Lung

• Ventilation is continuous, not cyclic
• Conducting airways function as inert tubes
  carrying the vapor to the gas exchange region
• Diffusion of vapor across the lung cell and
  capillary walls is perfusion-limited
• All xenobiotic disappearing from inspired air
  appears in arterial blood
• Vapor in the alveolar air and arterial blood
  within the lung compartment are in rapid
  equilibrium

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Liver

• Hepatic biotransformation
• Assumed to be flow-limited
• Saturable metabolism

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Conclusions

• Expansion of physiologic modeling
• Physiologically based toxicokinetic models
• Linked with biologically based toxicodynamic
  models

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Question 1 Which of the following is not true of
physiologically based models?

• A) can provide time course distribution of
  xenobiotics to any organ or tissue
• B) can predict the toxicokinetics across species
• C) do not allow dose regimens and saturable
  processes to be incorporated into the model
• D) they allow estimation of the effects of
  changing physiological parameters

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Question 2 Which of the following is true
regarding first order elimination?

• A) the rate at which a chemical is eliminated at
  any time is directly proportional to the amount
  of that chemical in the body at that time
• B) a semilog plot of concentration versus time
  yields a straight line
• C) the elimination rate constant is independent
  of dose
• D) all of the above
• E) none of the above