L35 - Drug Distribution 2

• How can body exposure to a drug be expressed?

  - [drug] conc (Cp) at a given time.

  
  

  - Area Under Curve (AUC) where y= [drug] and x = time

  
• Give an equation to calculate dose.

  Dose = Volume x [conc] required

  
• What is [drug] conc in plasma a function of?

  Dose given, elimination kinetics and extent of drug distribution into tissues (Vd).
• Define Volume of Distribution (Vd)

  The volume into which the drug distributes in the body once the equilibrium of distribution has been achieved.

  
• What's the equation for Volume of Distribution (Vd)?

  Vd = Amount of Drug in body (A) / [drug] conc in plasma (Cp)

  
• Why is Vd used?

  - To relate the amount of drug in the body with the [drug] conc in plasma (Cp)

  
  

  - To estimate the dose required to achieve a given conc

  
• Give the equation for Volume of Distribution linking plasma/tissue volume.

  Vd = plasma vol. + tissue vol. x (tissue conc/plasma conc).

  
• What happens to the Vd the larger the amount of unbound drug in plasma?

  The larger the amount of unbound drug in plasma (fUnbound), the larger the volume of distribution.
• What happens to Vd the larger the binding in tissue?

  The larger the binding in tissue, the larger the Vd.
• What equation describes the amount of drug in plasma?

  Amount of drug in plasma = plasma vol x plasma [conc]
• What equation describes the amount of drug in tissue?

  Amount in tissue = tissue vol x tissue [conc]
• What's an equation for Vd that links the partition coefficient, P?

  Vd = (plasma vol + tissue vol) x P

  
• Define extravasation.

  
  

  What size of drug has very little?

  unintentional leakage from blood vessels.

  
  

  Very large drugs have very little extravasation.

  
• How can we calculate % of drug present in plasma?

  = Volume of plasma / Vd x100

  
• How can we calculate % of drug present in tissues?

  = Vd - vol of plasma / Vd x 100

  
• Give an equation for Vd lonking plasma/tissue vol and fUNbound.

  Vd = vol. plasma + vol. tissues x (fu/fu tissue)

  
• When is the equilibrium of distribution obtained?

  When conc [unbound] = conc [unbound] in tissue.

  
  

  
  

  OR

  
  

  
  

  when [drug] in tissue = P x [drug] in plasma.

  
• When do binding events occur?

  when conc of free drug in plasma and tissue are the same.
• When does partitioning occur?

  when [drug] conc in tissue = P x [drug] conc in plasma
• What 2 factors can drug distribution be limited by?

  1. Permeability of drug across membrane (diffusion).

  
  

  2. Perfusion (blood flow).
• What is permeability rate-limited diffusion?

  
  

  What modifies distribution?

  Drugs diffuse slowly across membranes, eg polar drugs diffusing across tight junctions in BBB.

  
  

  Tissue access is rate limited by diffusion of drug across membrane.

  
  

  - changes in membrane permeability modify distribution.

  
  

  - kinetics of distribution very dependent on drug properties.
• What is perfusion rate-limited distribution?

  
  

  What limits access to tissues?

  
  

  What modifies distribution?

  Distribution limited by rate of blood flow.

  
  

  Well perfused tissues take up drug faster than poorly perfused.

  
  

  Changes in blood flow modify distribution.
• Kinetics of Perfusion rate-limited distribution:

  What are the eqns for rate in/rate out?rate in = blood flow (q) X [artery] conc.

  
  

  
  

  rate out = blood flow (q) X [vein] conc.

  
• Give the eqn for perfusion rate.

  Perfusion rate = blood flow (q) / volume in tissues (Vt)

  
• How can we calculate rate of uptake?

  rate = (Q x Ca) - (Q x Cv) = Q(Ca-Cv).

  
  

  Where QxCa = how rapidly drug arrives to tissue.

  
  

  and QxCv = how rapidly drug leaves tissue.

  
• What's Kt?


  Tissue Distribution Rate Constant, Kt = rate of drug exit from tissues, divided by amount of drug in tissue.

  
• What's the eqn for Kt?

  Kt = rate of exit / amount in tissue

  
  

  = Q / Vt x P.

  = (Q/Vt) / P.

  = perfusion rate / tissue or plasma ration

  
• What does the tissue distribution rate constant (Kt) tell us?

  
  

  What happens to distribution the larger the K?

  Kt tells us how quickly the distribution process occurs for a drug/tissue.

  
  

  The larger K, the faster distribution occurs.
• Give the eqn for tissue distribution half life (t1/2).

  
  

  How does it affect distribution?

  t1/2 = 0.693 / Kt.

  
  

  
  

  The larger t1/2, the slower distribution

  
• When does fast distribution occur?

  
  

  How does this affect Kt and t1/2?


  - Tissues have high perfusion (Q/Vt).

  
  

  - Tissues have low affinity for the drug (low P).

  
  

  Kt = high, t1/2 = low.
• When does slow distribution occur?

  
  

  How does this affect Kt and t1/2?

  - Tissues have low perfusion (Q/Vt). eg fat - receives small amount of drug per unit time.

  
  

  - Tissues have high affinity for drug (high P).

  
  

  Kt = low, t1/2 = high.
• What level of tissue perfusion achieves Vd faster?

  Tissues with higher perfusion obtain Vd for a drug faster.

  
  

  Low affinity - so only needs short amount of time to reach suffiecient amount of drug.