VM 8314

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VM 8314
Drug Distribution
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”
Tissue
Vascular
ICF
ECF
ECF
ICF
Dr. Wilcke
VM 8314
Physical and
Physiologic “spaces”
Point to:
Tissue ECF
Tissue ICF
Vascular ECF & ICF
Dr. Wilcke
VM 8314
Vascular space
 ~ 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
Tissue space
 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
Extracellular space
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
Intracellular space
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
Reserved spaces
“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
Movement between spaces
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
Movement between spaces
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
Enterohepatic circulation
= drug molecule paths
Dr. Wilcke
VM 8314
Enterohepatic circulation
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
Enterohepatic circulation
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
Enterohepatic circulation
Why do you care?
Interrupt to improve drug elimination
Poisonings, barbiturate overdoses, etc.
Dr. Wilcke
VM 8314
Mammary excretion
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
Salivary excretion
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
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