Tissue distribution

Question 1

What is tissue binding characterised by?

Answer 1

Tissue-to-plasma partition coefficient (Kp)

Question 2

What is Vtw?

Answer 2

Aqueous volume outside the plasma (12-39L) = extracellular space in tissues + cellular space

Question 3

What is the equation relating amount of drug in the body to amount IN plasma and OUT of plasma?

Answer 3

A=V.C=Vp.C=Vtw.Ct

Question 4

What does the Volume of distribution equal in relation to fraction unbound in tissues etc?

Answer 4

V=Vp+Vtw x (fu/fut)

Question 5

What would happen to the volume of distribution if the fraction unbound in plasma is high?

Answer 5

Ratio will be greater than 1 - will result in a higher V

Question 6

What would happen to the volume of distribution if the fraction unbound in tissues is low?

Answer 6

Low fut (extensive tissue binding) would drive to a high V (dividing by a smaller number)

Question 7

What would a linear relationship between Vp and fu suggest?

Answer 7

All other parameters are constant

Question 8

Furosemide and amiodarone have fu of 0.02 and 0.04, respectively. Respective volume of distributions of these 2 drugs are 10 and 7000L. Provide explanation for much larger V of amiodarone

Answer 8

Amiodarone has a much lower fut, i.e. higher tissue binding than furosemide.

V=Vb+Vtw.(fub/fut)

Question 9

Based on the high Volume of distribution of amiodarone, is it acidic or basic?

Answer 9

Basic because basic drugs bind to components like acidic phospholipids

Question 10

• Digitoxin has volume of distribution of around 40L (volume of body water), yet it is known to bind strongly to cardiac tissue. How do we explain value of its V?

Answer 10

Volume of distribution of digitoxin is equal to total body water and would suggest no tissue accumulation, which is misleading in this case.

Question 11

What transporters mediate uptake of drugs into the hepatocyte?

Answer 11

e.g. OATP1B1 transporters uptake atorvastatin from blood into hepatocyte. Can result in Cliver»Cplasma - beneficial for statins

Question 12

What transporters mediate excretion of drug into the bile?

Answer 12

Efflux transporters e.g. excretion of rosuvastatin by BCRP

Question 13

When does concentration of unbound in plasma NOT equal concentration of unbound in the tissues?

Answer 13

• If active transport and/or rapid metabolism occurs.

- Rapid metabolism in the tissue reduces concentration in the tissue and drives concentration from plasma into the cell

Question 14

What reduces tissue concentration?

Answer 14

Efflux transporters such as Pgp

Question 15

What increases tissue concentration?

Answer 15

Uptake transporters

Question 16

How can Kp (tissue-to-plasma partition coefficient) be determined?

Answer 16

o in vitro – using tissue homogenate or isolated perfused organs (in preclinical species – use this data to estimate V in humans)
o in silico – predictive equations based on physicochemical properties of the drug and tissue composition (in some cases, animal tissue composition data are used)

Question 17

What model is used to represent organ compartments etc and blood flow?

Answer 17

PBPK modelling: considers all parameters of drug and physiology etc. Used to predict DDIs and prediction of PK