1. VM 8314 Dr. Wilcke Drug Distribution

2. VM 8314 Dr. Wilcke  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 Physiologic “spaces”

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

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

5. VM 8314 Dr. Wilcke 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.

6. VM 8314 Dr. Wilcke 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)

7. VM 8314 Dr. Wilcke 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

8. VM 8314 Dr. Wilcke 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

9. VM 8314 Dr. Wilcke 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.

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

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

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

13. VM 8314 Dr. Wilcke “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

14. VM 8314 Dr. Wilcke “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

15. VM 8314 Dr. Wilcke Enterohepatic circulation = drug molecule paths

16. VM 8314 Dr. Wilcke 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)

17. VM 8314 Dr. Wilcke 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)

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

19. VM 8314 Dr. Wilcke 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…

20. VM 8314 Dr. Wilcke 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