Factors affecting Distribution

Vascular Factors

• Drugs diffuse from capillary beds—> interstitial —> intracellular space.
• More vascular (e.g. heart, lung, kidney) = more drug delivered to them than others (e.g. skin, bone, fat).
• Capillary leakiness:
  • Some capillary bed epithelial cells are fenestrated by 60-80nm diameter pores (e.g. intestinal, endocrine, pancreatic and kidney).
  • In others endothelial cells are separated by slit junctions or large intercellular gaps to allow large movements of molecular material (Liver, bone marrow, lymph nodes, spleen).
  • These ‘leak’ points facilitate access to the interstitial fluid.

Drug factors

• Ease of crossing phospholipid bilayers
• Interactions with lipid tissue (lipophilic = more distribution into fat)
• Interactions with protein

| Lipophilic vs lipophobic (Or Hydrophobic vs hydrophilic) | - More lipophilic (hydrophobic) molecules diffuse out of plasma into surrounding tissues.

• They will also favour distributing to lipid-rich tissues.   If the drug has a net negative charge, it can still leave the capillaries through endothelial fenestrations, but further tissue penetration depends on:
• Interstitial fluid pH
• Drug pKa
• Presence of OAT/OCT carriers | | --- | --- | | Plasma protein binding | There are several plasma proteins that bind drugs, but the main protein is albumin:
• Each albumin molecule contains several binding sites, & binds drugs with weak electrical polar bonds, allowing
  1. Storage/transportation of ‘bound’ drug
  2. Quick release of the drug to become ‘free drug’.
• Only free drug distributes out of plasma, has a pharmacological effect etc.
• The proportion of bound:unbound drug remains the same regardless of concentration.

e.g. Aspirin is 50% protein bound - therefore:

• At 1mM plasma concentration, 0.5mM is protein-bound
• At 0.1mM plasma concentration, 0.05mM is protein-bound | | Tissue protein binding (e.g. muscle) | - This ‘drains’ the drug from plasma.
• This will in turn reduce amount of plasma free drug. | | Tissue binding sites | - Digoxin has a high affinity for Na+/K+-ATPase, so disseminates to tissue containing this; first skeletal, then cardiac muscle and kidney.
• More muscular individuals will have more Na+/K+-ATPase on skeletal muscle fibres. Digoxin will distribute out of plasma to muscle; they will have a higher volume of distribution. ·       Less muscular patients (e.g. the elderly) will have less distribution to skeletal muscle, leading to a lower volume of distribution and therefore a higher concentration of plasma digoxin; they will be more susceptible to toxicity. |

Body fluid compartments & compartment models

Main fluid compartments in the body (as a proportion of the ‘70kg male’ TBW):

Where a drug distributes to depends on the major factors listed above.

• In 1 compartment model the drug is assumed to instantly distribute to all body fluid. This is overly simplistic, but describes the distribution of many drugs.

• In 2-compartment modelling there is:

  • The central compartment (Plasma)
  • A peripheral compartment (ICF & interstitial fluid).

  For drug to be eliminated from the body, it has to move from the peripheral back to the central compartment, where it can be metabolised & excreted.

• There are multi-compartment models beyond this

The Volume of Distribution, Vd