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Dr. Wilcke

Drug DistributionDrug Distribution

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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)

Physical and Physical and Physiologic “spaces”Physiologic “spaces”

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Dr. Wilcke

Physical and Physical and Physiologic “spaces”Physiologic “spaces”

ICF ECF ECF

ICF

Vascular Tissue

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Dr. Wilcke

Physical and Physical and Physiologic Physiologic “spaces”“spaces”

Point to:

Tissue ECFTissue ICFVascular ECF & ICF

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Dr. Wilcke

Vascular spaceVascular 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.

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Dr. Wilcke

Tissue spaceTissue space the rest of the volume (water)

neither structural proteins nor bone matrix (no water)

EquillibriaWater ↔ 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)

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Extracellular spaceExtracellular spacePresent in both vascular and

tissue spaces~15 – 20% of body (by weight) Larger in neonates

EquillibriaIonized and unionized (Protein) bound and unbound

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Intracellular spaceIntracellular spacePresent in both vascular and

tissue spaces~35 – 45% of body (by weight)

EquilibriaIonized and unionized drug

Distribution in 30 minutes to +12 hours

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Dr. Wilcke

Reserved spacesReserved spaces“Protected tissues”

CSFAqueous humorProstatic fluid

Distribution in minutes to neverMost dosing situations not

relevantImportant if the disease is in the

reserved space.

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Movement between Movement between spacesspacesVascular (ECF) ↔ Tissue (ECF)

Transcytotic http://www.bio.davidson.edu/people/kabernd/BerndCV/Lab/EpithelialInfoWeb/Transc

ytosis.html

Endothelial junctionsEspecially with inflammation

DiffusionCarried in WBCs (rare)

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Movement between Movement between spacesspacesECF to ICF

DiffusionActive uptake

WBCs seem to be particularly able…

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Dr. Wilcke

““Diffusion limited” Diffusion limited” distributiondistributionIn general, diffusion is the

rate-limiting step drug distribution TO the tissues

ECF ↔ ICF

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““Blood flow limited” distributionBlood flow limited” distribution

IF diffusion is rapidTissue 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 uniformBrain and kidneys - high portion of flowMuscles intermediateSkin and fat - small portion

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““Blood flow limited” Blood flow limited” distributiondistributionUltra-short acting barbiturates

Brain is saturated FIRSTMuscle is saturated LATER

Animals wake up because the muscle keeps soaking up drug (not because drug is metabolized)Not all barbituratesDoes not apply to gas anesthetics

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Enterohepatic circulationEnterohepatic circulation

= drug molecule paths

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Enterohepatic circulationEnterohepatic circulationHow does it work

Drug taken up by liver cellsDrug or phase II conjugate excreted

in bileDrug reabsorbed from intestine

(Phase II conjugate cleaved to liberate drug if necessary)

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Enterohepatic circulationEnterohepatic circulationWhat does it mean

Volume of distribution is increasedThe 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)

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Enterohepatic circulationEnterohepatic circulationWhy do you care?

Interrupt to improve drug eliminationPoisonings, barbiturate overdoses, etc.

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Mammary excretionMammary excretionDistribution from one perspective

Simple diffusion of unionized drugIon trapping (normal milk is slightly acidic v blood)

Inflammation reduces barrierElimination from another

Drug actually does leave the body if it’s in milkJust not much of it

(Absorption from a third ;-)If you’re the baby…

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Salivary excretionSalivary excretionDistribution from one

perspectiveDrug in saliva is likely to be absorbed

from GI tractActs very much like enterohepatic

circulationActually important in ruminants

Elimination from anotherDrug is probably not 100% absorbed

from GI tract