5: Distribution, Protein Binding

free drug hypothesis

only unbound/free drugs diffuse and have pharmacological effects (only free drugs in plasma get to organs of elimination)

2 steps of distribution, define them

1. delivery: blood filtration (tissue perfusion)

2. uptake: passage/transport into organ (diffusion & membrane permeability)

increased blood filtration means what

increased drug distribution

where is distribution faster

to highly perfused tissues (also faster to leave)

what type of passage is distribution mainly driven by

passive diffusion (depends on physiochemical properties of drug & permeability of cell)

when would transporters be used in distribution

when drug needs to get into certain organs/tissues (e.g., BBB has efflux transporters but also uses uptake transporters to let certain drugs into brain)

plasma L

3 L

ECF L

15 L

what fluid compartment in the body do most drugs distribute to and why?

ECF, vascular membrane is loose

TBW in L

40 L

properties of drugs that distribute to intracellular fluid

lipophilic, substrates of uptake transporters

What does Vd describe

extent of distribution

(theoretical volume a drug would occupy at its plasma concentration → NOT REAL VOLUME)

what does binding to plasma proteins do?

inhibit distribution from the plasma to the tissue

small Vd means

drug is preferentially bound to plasma protein

(or that drug doesn’t access certain volumes in the body)

If a drug binds to plasma proteins can we assume it will have a small Vd?

no

decreased protein binding effect on unbound drug

increases unbound drug

(more availability for therapeutic effect but higher toxicity risk)

what happens when a drug binds to tissues

Cp decreases → large apparent Vd

large Vd meaning

drug binds extensively to tissues (most of drug in body can be found in tissues)

when is a drug retained in space outside plasma

1. bound to tissues

2. partitioning of a lipophilic drug into fat

what happens when a drug’s Vd is > TBW?

(TBW = 40 L)

the drug is preferentially retained in tissues

(or space outside plasma)

if a drug has large Vd, how does it eliminate and why

large Vd = large t1/2, therefore slow elimination

what drugs does albumin bind

acidic or neutral drugs

what causes decrease in albumin

liver/renal disease, burns, pregnancy (3rd trimester)

what kind of drugs does AAG bind

mostly basic

(some acidic or neutral drugs: propranolol, quinine, digoxin, streptomycin)

what causes AAG increase

inflammatory disease, trauma

acute phase reaction protein (stress, MI, cancer)

is protein binding reversible

yes (association and dissociation maintains equilibrium)

do bound or unbound drugs diffuse from plasma?

only unbound drugs can diffuse from plasma and interact with receptors (response) and enzymes (elimination)

what happens to binding when Cp increases?

binding also increases (proportional to Cp)

when does fu change?

1. change in protein concentration

2. displacement by other drugs

3. burns

how does fu change if protein concentration decreases?

fu increases

(albumin decrease → fu increase; AAG increase → fu decrease)

how does drug displacement impact fu?

large concentrations of other drugs can displace pre-existing drug-protein complexes → increase fu

what clinically occurs when fu increases?

Cpu increases → body compensates by increasing elimination → Cp decreases, Cpu returns to normal

(the speed of this depends on drug’s elimination rate)