Distribution

Question 1

Vessels in distribution

Answer 1

Lymphatic system can drain into the systemic circulation.

Capillaries distribute the drug throughout the body. The single cell layered wall allows passage of drugs between the blood and tissues.

3 types of capillaries: continuous (nerves and muscle), fenestrated (glomerular and gut), and discontinuous (liver and marrow).

Question 2

Determinants of rate of distribution.

Answer 2

Perfusion (how quick the drug reaches the tissue), permeability (how well the drug is distributed to the tissue), PPB, binding of drug to tissue components or adipose.

Perfusion rate is the rate limiting factor with small and lipophilic drugs: they would have good permeability.

Conversely permeability is likely to be the rate limiting factor in polar molecules, and impermeable membranes (e.g., BBB). Also the case for highly ionised drugs.

Question 3

Mechanism of BBB exclusion of drugs, and factors of drug determining permeability

Answer 3

The BBB is glial cells wrapped around the blood vessels, with tight endothelial junctions, and they lack endothelial gaps/channels.

Lipophilicity and degree of ionisation determine BBB distribution. More lipophilic the better, the less ionised the better. More limited permeability for polar drugs.

Question 4

Extent of distribution (Vd) and relationship with [plasma]

Answer 4

Measured by apparent volume of distribution (V) measures plasma [drug] to the total amount of drug in body. Inverse relationship, a lower plasma [drug] for same dose identifies high V.

Question 5

Plasma protein binding (PPB) examples

Answer 5

Often bind to specific drugs. Albumin (HSA) commonly binds acidic drugs. alpha-1 acidic glycoprotein commonly binds basic drugs. Globulins bind steroids.

PPB is non-covalent. Reversible and rapid.

Generally increases in lipophilicity increases PPB.

Fu identified the fraction of unbound drug.

Question 6

factors of the drug that determine Tissue binding

Answer 6

Acids often highly PPB. Low binding to tissues.

Bases often have high tissue affinity.

For neutral drugs, the PPB and tissue binding is driven by lipophilicity.

Question 7

what factors of drug cause Drug accumulation in different regions

Answer 7

Can accumulate in components of tissues or adipose.

Lipophilic drugs accumulate in the adipose.

Basic drugs can accumulate in the lysosomes of cells. This is due to low pH in lysosomes, which ionises the basic drugs, trapping them within the organelle.

Question 8

roles of Transporters in distribution

Answer 8

Pgp for CNS exclusion, e.g., loperamide, cetirizine

OATP1B1 allows the uptake of pravastatin to enable reductions in cholesterol production via the inhibition of HMG-CoA reductase

OCT1 uptake of metformin into the liver