Introduction to Veterinary Pharmacokinetics:

Drug Distribution

Physical and Physiological "spaces"

At a high level (gross anatomy?) we divide the body into:

Vascular space = plasma / plasma water + RBCs (lots) +WBCs (a few)

  • Don't forget the intracellular space inside the vascular space...
  • ~ 7% of body weight
  • mixing in 2 - 20 minutes

Tissue space (intracellular fluid / cells)

  • The rest of the body water (not structural protein, bone matrix)
  • Equillibrium with bloodstream in 30 minutes to several doses (hours/days)

Extracellular Space - exists in both vascular and tissue spaces

Size

  • ~ 15 - 20% of  body weight
  • includes extracellular fluid in bloodstream (plasma)
  • Distribution in 30 minutes to 1.5 hours

Intracellular space - exists in both vascular and tissue spaces

Size

  • ~ 35 - 45% of body weight
  • Distribution may not occur and it can take days

Reserved spaces

Special barriers between plasma and tissue fluid

  • CSF
  • aqueous humor
  • prostatic fluid
    • Distribution in minutes to never
    • Most dosing situations -> irrelevant because they are so small
    • Important if the disease is in the reserved space

Equillibria

Vascular Space

  • between water and various plasma / serum proteins
  • between ionized and unionized drug
  • between plasma and cells

Tissue space

  • between water and various tissue proteins
  • between ionized and unionized drug
  • between water and cells

Extracellular

  • between water and proteins
  • between ionized and unionized drug

Intracellular

  • between unionized (active) and unionized (trapped) drug

Between ICF and ECF

  • intracellular pH different (lower) than extracellular

Movement between spaces

Vascular space (extracellular) to tissue (extracellular) space

Extracellular space (of tissue) to intracellular space (of tissue)

Vascular extracellular space to vascular intracellular space (drugs can move into RBCs and WBCs)

Diffusion limited distribution
Blood flow limited distribution

Enterohepatic circulation

SOME drugs get recycled liver->bile->intestine->portal circulation->liver. This makes the volume of distribution larger because the drug leaves the bloodstream termporarily. SOMETIMES, you can increase elimination by giving an animal activated charcoal to bind the drug in the gi tract.

How does it work?

  • Drug or it's Phase II conjugate excreted in bile
  • Drug reabsorbed or Conjugate cleaved by bacteria and drug reabsorbed

What does it mean?

  • Volume of distribution of the drug is higher
  • Elimination rate for drug is lower in spite of efficient hepatic metabolism / secretion

Why do you care?

  • Interrupt to improve drug elimination
  • Insecticide poisonings, phenobarbital overdoses, etc.
Enterohepatic circulation

Mammary excretion

Its best to remember that some drugs given to moms end up in milk. Especially important for nursing infants. Especially important for drug residues. Not important for distribution. Not important for elimination. Might not even be important for therapy of mastitis.

How does it work?

Why do you care?

Salivary excretion

Drug molecules in saliva can be used for "drug testing." If this occurs, it can affect distribution and elimination of drugs in ruminants (any route of administration). Lower volumes of saliva means that such an effect is unlikely in other animals.

How does it work?

What does it mean?

Ruminants

Non-ruminants