L34 - Drug Distribution 1

• Define Tissue Perfusion


  blood flow per unit and mass of tissue
• Define drug distribution,

  
  

  What enables good distribution?

  
  

  What is often the rate limiting step for drug distribution?

  reversible transfer of a drug from one site to another within the body.

  
  

  Efficient drug distribution is enabled by blood circulation.

  
  

  RDS = tissue distribution! Rate and extent of distribution depends on drug and tissues. Mixing of blood is fast.
• Define cardiac output


  amount of blood the heart pumps through the circulatory system in a minute.
• Which organs receive a high proportion of cardiac output?

  Liver and kidneys bc they're eliminating organs, so receive drugs faster.
• What are the 2 main steps in drug distribution?

  1) Passage of capillary membrane.

  
  

  2) Passage of cell membrane.

  
• What influences paracellular diffusion?

  Intracellular junction tightness

  
• What is transcellular diffusion divided into?

  simple diffusion pathways, and pathways involving transporters.

  
• What's the Noyes-Whitney eqn describing Fick's Law?

  Where D = diffusivity/diffusion coefficient.

  P = partition coefficient.

  A = particle SA.

  h = membrane thickness.

  Cs = drug solubility.

  Cb = [drug] in bulk solution.

  
• How are drugs distributed from blood to interstitial fluid?

  
  

  Easy/hard?

  - paracellular, easily.

  
  

  - through capillary membrane.

  
  

  - independent of lipophilicity, charge, molecular size (up to 5000g/mol).

  
  

  - charge important for larger molecules (eg -ve molecules show lower permeability across renal glomerulus.
• How are drugs distributed from interstitial fluid to cell?

  
  

  Easier or harder than from blood to interstitial fluid?

  - harder, as cell membranes not as leaky.

  
  

  - passage depended on drug physicochemical properties AND/OR the drug being a substrate for influx/efflux pump transporters.
• What is transport dependent on across blood-brain barrier, hepatocyte and renal tubule?

  lipophilicity, charge and molecule size.
• What's the effect of charge and pH on membrane transport?

  - membrane transport slower for charged drugs.

  
  

  - the degree of ionisation at physiological pH also determines movement across membranes.
• What is the pH partition hypothesis?

  only unionised drugs can permeate membranes (more lipophilic).

  
• Equilibrating vs Active transporters: what do they do?

  Equilibrating = passive/facilitated transport. End point when [drug] conc on either side of membrane is the same.

  
  

  Active = move drug to side of membrane with higher [drug].

  
• Transporters in the Blood-Brain Barrier (BBB)


  - what is transport dependent on?- what happens to permeability as lipophilicity increases?- where is [drug] usually higher: plasma or CSF?- dependent on size, lipophilicity, Mw.

  
  

  - as lipophilicity increases, permeability increases.

  
  

  - [drug] usually higher in plasma than CSF.

  
• Suggest why vinblastine/vincristine have a lower permeability (see graph)

  Bc they're substrates for the efflux transporter PGP which transports them out of the cell.

  
• What is plasma binding?


  determinant of drug distribution due to increased Mw.
• What can drugs bind to?

  tissue components, plasma proteins, erythrocytes
• Different drugs bind to different plasma proteins.

  
  

  Eg, what do acidic/basic/neutral drugs mainly bind to?

  - Acidic = albumin (most abundant).

  
  

  - Basic = 𝛂1-acid glycoprotein.

  
  

  - neutral = lipoproteins.
• Why can't bound drugs diffuse across membranes?

  Bc plasma proteins can't! Often Mw is too big.
• How do we describe the degree of binding for a drug?

  
  

  At what value is a drug considered highyl bound?


  Using it's Bound fraction (fBound).

  
  

  - value is 0-1.

  
  

  - a drug is highly bound when fBound > 0.9.
• What's the equation for fBound?

  
  

  fUnbound/fFree?

  fBound = [drug] bound / [drug] total.

  
  

  fUnbound = [drug]free / [drug]total.

  
• How do we find the concentraition of the free/fUnbound [drug] in plasma?

  Cfree = Ctotal - fUnbound

  
• How are bound and unbound commonly expressed?

  unbound = 𝛂 and bound = β
• How does drug binding modify drug distribution?

  
  

  What is distribution dependent on?

  - Drug-Protein complex is too large to diffuse across membranes.

  - only free drug can distribute out of plasma.

  - Distribution is dependent on the drug's binding affinity to BOTH the plasma and tissue components.

  - Equilibrium is reached: [drug]Unbound intissue= [drug]Unbound inplasma

  
• How do we describe a drug's affinity for a tissue?

  Through a tissue/blood partition coefficient: (similar to octanol/water).

  
  

  Ptissue/blood = [drug] in tissue / [drug] in plasma.

  
  

  
  

  Eg for a drug w/ Ptissue/plasma = 10, the [drug] in tissue will be 10 x [drug] in plasma for equilibrium of distribution to be achieved.

  
• How do we determine partition coefficient?

  Mix tissue and blood and allow them to separate.

  
  

  Measure [drug] in tissue and blood - resulting ratio gives the partition coefficient.