Volume of distribution

Question 1

Extent of distribution:

Answer 1

• Defined by apparent volume of distribution (V)
• Based on equilibrium concept
• Relates measured plasma (or blood) drug concentration (C) to the amount of drug in the body (A) at the equilibrium

Question 2

Volume of distribution:

Answer 2

Amount of drug in the body at equilibrium/ Drug conc in the plasma

Question 3

Apparent volume that the drug occupies at a concentration_________:

Answer 3

Equal to that in plasma

Question 4

Volume of distribution varies across drugs ________ L.

Answer 4

3 to 40000L

Question 5

Total body water:

Answer 5

40L

plasma water 3L, extracellular water 12L

Question 6

Why may Cb ,C and Cu differ?

Answer 6

Cb, C and Cu can differ as a consequence of binding of drugs to cells and plasma proteins

Question 7

Cb, C and Cu at equilibrium=

Answer 7

A (amount) = V x C = Vb x Cb = Vu x Cu

Question 8

Clinical relevance of V?

Answer 8

important PK parameter to determine the loading dose of a drug (loading dose = initial dose)

Question 9

General trend in volume of distribution?

Answer 9

• General trends – monoclonal AB’s tend to have low VOD’s and tend to reside in the plasma
• Acidic drugs tend to be highly ionized and bind extensively to plasma proteins which gives a lower VOD
• And vice versa with basic drugs and bind to acidic phospholipids in other tissues which gives the higher VOD

Question 10

What affects the value of volume of distribution?

Answer 10

 Drug can bind to plasma proteins, blood cells and tissue components!
 Acids (e.g., warfarin) show strong affinity for plasma proteins
 Basic drugs (e.g., fluoxetine) generally have higher V
 High affinity for acidic phospholipids in tissues
 Monoclonal antibodies – tend to reside in plasma

Question 11

What is sub-cellular distribution?

Answer 11

Lysosomes:

• Sequester cationic amphiphilic drugs (LogP>2, pKa 6.5-11) (lungs, liver) reduced the ability of the protonated drug to diffuse back into the cytosol.
• Drug trapped in cytosol due to ph of lysosome
• Antibody drug conjugates

Question 12

Subcellular distribution implications?

Answer 12

 Prerequisite for therapeutic efficacy - antimalarials

• Reduced activity and off-target effects
• Vinblastine
• Azithromycin
• Safety issues – phospholipidosis

Question 13

Plasma protein factors:

Answer 13

• Generally a reversible process, very rapid
• Drug + Protein Drug-Protein complex

Representative proteins to which drugs bind in plasma:

• ALBUMIN - acidic (e.g., warfarin) and neutral drugs (e.g., cyclosporine)
• a1- ACID GLYCOPROTEIN - basic drugs
• GLOBULINS - steroids

Question 14

Fu =

Answer 14

fraction of drug unbound in plasma (Cu/C)

Question 15

1-Fu =

Answer 15

fraction of drug bound

Question 16

Fu is determined experimentally; it depends on:

Answer 16

• Affinity of the protein for the drug (Ka)

- Protein and drug concentration

Question 17

Why is knowing the fu of a drug so important?

Answer 17

• Total plasma concentration (C) is usually measured
• When fu is constant - changes in total plasma concentration reflect changes in the unbound drug concentration (C= Cu/fu)
• Fu may change in pregnancy or in some diseases (liver cirrhosis, renal impairment)

Question 18

All drugs bind, true or false?

Answer 18

False

Question 19

Why is the unbound drug concentration important?

Answer 19

Assumption – only unbound drug diffuses into tissues in order to have pharmacological effect or to be eliminated

Question 20

Summer of VoD

Answer 20

• Drug may bind to plasma proteins, blood cells and/or tissue components
• V is an important pharmacokinetic parameter to determine the loading dose
• Only unbound drug moves across the membrane and diffuses into tissues