Absorption, Distribution, and Excretion of Toxicants

• ADME


  Absorption, Distribution, Metabolism, and Excretion
• ADBE

  Absorption, Distribution, Biotransformation, and Excretion
• Absorption

  Often via mucous surfaces like the digestive tract (intestinal absorption) – before being taken up by target cells

  
• Distribution


  The compound needs to be carried to its effector site, most often via the bloodstream. From there, the compound may distribute into muscle and organs etc.
• Metabolism

  The initial (parent) compound may be broken down or converted to new compounds called metabolites
• Excretion


  Compounds and their metabolites need to be removed from the body via excretion, usually through the kidneys (urine) or in the feces
• Determinants of Toxicity


  • Inherent nature and reactivity of chemical
  • Concentration and duration in target organ
• Dose


  The amount of a substance administered
• Disposition


  • Absorption
  • Distribution
  • Metabolism/Biotransformation
  • Excretion
• 3 major exposure routes: inhalation, dermal, ingestion (also injection)
• The absorption, distribution, and elimination of a chemical


  Determine the concentration at the site
• The concentration at the site

  Is proportional to the dose received
• 2 chemicals of the same dose but differing metabolism


  Would result in different concentrations at the target site
• Elemental Hg


  • Low skin absorption
• MeHg (methyl mercury)


  • Rapidly absorbed
• A chemical can be distributed to tissue and stored there


  Resulting in decreased concentration at the target site (e.g. Pb, PCBs)
• Biotransformation


  Can decrease the concentration of the chemical at the target site
• Faster elimination


  Lower concentration
• Toxicokinetics


  What the body is doing to the chemical
• Toxicodynamics


  What the chemical is doing to the body
• Classical toxicokinetics


  The disposition of a chemical is described by its concentration in the plasma with respect to time

  
• Physiologic Toxicokinetics


  The disposition of a chemical is described in specific organ/tissue compartments
• Physiologic Toxicokinetics


  • Can provide the time course of distribution of xenobiotics to any organ
  • Allows for the estimation of the effects of changing physiologic parameters on tissue concentrations
  • The same model can predict the toxicokinetics of chemicals across species
  • Complex dosing regimens and saturable processes (metabolism or binding) are easily accommodated

  
• One compartment model

  The body consists of one compartment
• Two-compartment model


  The body consists of two compartments - a central and peripheral compartment – each exhibiting different kinetics

  
• Half life (t1/2)

  The time it takes for the concentration of a chemical to decrease by half
• Absorption


  Dependent on: size of molecule, lipid solubility, degree of ionization
• Specialized Transport


  • Active transport
  • Pinocytosis and phagocytosis
  • Xenobiotic transporters
  • Facilitated diffusion

  
• Active Transport


  Movement of chemicals against electrochemical or concentration gradients, Saturability at high substrate concentrations, Selectivity for certain structural features of chemicals, Competitive inhibition by chemical compounds that are carried by the same transporter, Requirement for expenditure of energy
• Xenobiotic Transporters


  Responsible for the uptake of some chemicals into cells, and extremely important for the export of chemicals out of cells
• Capillary Permeability


  • Blood-brain Barrier: Only lipophilic drugs diffuse across brain capillaries
  • In liver and spleen, the capillaries are very leaky
  • In other tissues, selective capillary permeability varies somewhere between the above two extremes
• Epidermis (Skin)


  • Stratum corneum is the rate limiting layer and barrier layer
  • No blood vessels or lymphatics, local toxicity
  • Passive diffusion is the major mechanism
  • Permeability increases with hydration, abrasion, solvents etc.
• Dermis


  • Blood vessels and lymphatics are present, systemic toxicity
• Subcutaneous


  • Connective tissue and fat, minor systemic toxicity but has access
• Skin Designation

  TLV workplace "skin designation", Inhalation most important occupationally, Significant absorption can occur through the skin
• Pre-systemic elimination or first-pass effect


  The removal of chemicals before entrance into the systemic circulation (ingestion)
• Factors Affecting Xenobiotic Absorption in Gastrointestinal Tract (GIT)

  • Ionization Status
  • Surface Area available for absorption
  • Lipid Solubility
  • Solubility in GI fluids
  • Transit time in GI Tract
  • Active Transport
• pH & Ionization


  • Many chemicals, including a large proportion of drugs, are weak acids (AH, proton (H+) donors) or bases (B, proton (H+) acceptors) and are ionized in aqueous solution
  • The pH at which a weak organic acid or base is 50% ionized is called its pKa or pKb
• pKa


  Acid dissociation constant
• pKb


  Base dissociation constant