VM 8314
Dr. Wilcke

VM 8314
Physical and
Physiologic “spaces”
 Vascular space =
 Plasma/plasma water + (extracellular space)
 Many RBC’s (intracellular space) +
 A few WBC’s (intracellular space)
 Tissue space
 Interstitial fluid (extracellular space) +
 Cells of the body (intracellular space)
Dr. Wilcke

VM 8314
Physical and
Physiologic “spaces”
Vascular
ICF ECF ECF
Tissue
ICF
Dr. Wilcke

VM 8314
Physical and
Physiologic “spaces”
Point to:
Tissue ECF
Tissue ICF
Vascular ECF & ICF
Dr. Wilcke

VM 8314
 ~ 7% of body weight (mammals)
 Equilibria
 Water
↔ plasma and serum proteins
 Ioniozed drug
↔ unionized drug
 Plasma water
↔ inside of WBCs and RBCs
 Uniform mixing and distribution in 10 to 30 minutes.
Dr. Wilcke

VM 8314
 the rest of the volume (water)
 neither structural proteins nor bone matrix (no water)
 Equillibria
 Water ↔ tissue proteins (e.g. albumin)
 Ionized drug
↔ unionized drug
 Extracellular fluid
↔ intracellular fluid
 Reaches equillibrium in minutes to hours (even days and weeks is possible)
Dr. Wilcke

VM 8314
 Present in both vascular and tissue spaces
 ~15 – 20% of body (by weight)
 Larger in neonates
 Equillibria
 Ionized and unionized
 (Protein) bound and unbound
Dr. Wilcke

VM 8314
 Present in both vascular and tissue spaces
 ~35 – 45% of body (by weight)
 Equilibria
 Ionized and unionized drug
 Distribution in 30 minutes to +12 hours
Dr. Wilcke

VM 8314
 “Protected tissues”
 CSF
 Aqueous humor
 Prostatic fluid
 Distribution in minutes to never
 Most dosing situations not relevant
 Important if the disease is in the reserved space.
Dr. Wilcke

VM 8314
 Vascular (ECF) ↔ Tissue (ECF)
 Transcytotic
 http://www.bio.davidson.edu/people/kabernd/BerndCV/Lab/EpithelialInfoWeb/Transcytosis.html
 Endothelial junctions
 Especially with inflammation
 Diffusion
 Carried in WBCs (rare)
Dr. Wilcke

VM 8314
 ECF to ICF
 Diffusion
 Active uptake
 WBCs seem to be particularly able…
Dr. Wilcke

VM 8314
“Diffusion limited” distribution
 In general, diffusion is the rate-limiting step
 drug distribution TO the tissues
 ECF
↔
ICF
Dr. Wilcke

VM 8314
“Blood flow limited” distribution
 IF diffusion is rapid
 Tissue saturation by the drug (reaching equilibrium) is controlled by drug delivery to tissue
 Drug delivery to tissues is controlled by blood flow
 Tissue blood flow is not uniform
 Brain and kidneys - high portion of flow
 Muscles intermediate
 Skin and fat - small portion
Dr. Wilcke

VM 8314
“Blood flow limited” distribution
 Ultra-short acting barbiturates
 Brain is saturated FIRST
 Muscle is saturated LATER
 Animals wake up because the muscle keeps soaking up drug (not because drug is metabolized)
 Not all barbiturates
 Does not apply to gas anesthetics
Dr. Wilcke

VM 8314
= drug molecule paths
Dr. Wilcke

VM 8314
 How does it work
 Drug taken up by liver cells
 Drug or phase II conjugate excreted in bile
 Drug reabsorbed from intestine
 (Phase II conjugate cleaved to liberate drug if necessary)
Dr. Wilcke

VM 8314
 What does it mean
 Volume of distribution is increased
 The cycle itself is a space where drug “remains”
 It takes longer to eliminate the drug than you might expect
 (for drugs excreted by the liver)
Dr. Wilcke

VM 8314
 Why do you care?
 Interrupt to improve drug elimination
 Poisonings, barbiturate overdoses, etc.
Dr. Wilcke

VM 8314
 Distribution from one perspective
 Simple diffusion of unionized drug
 Ion trapping (normal milk is slightly acidic v blood)
 Inflammation reduces barrier
 Elimination from another
 Drug actually does leave the body if it’s in milk
 Just not much of it
 (Absorption from a third ;-)
 If you’re the baby…
Dr. Wilcke

VM 8314
 Distribution from one perspective
 Drug in saliva is likely to be absorbed from GI tract
 Acts very much like enterohepatic circulation
 Actually important in ruminants
 Elimination from another
 Drug is probably not 100% absorbed from GI tract
Dr. Wilcke