Distribution

Question 1

What does the distribution of chemicals depend on (2)

Answer 1

1. the properties of the chemicals (solubility; tendency to bind to proteins)
2. physiological factors (blood flow; organ volumes; enzyme activity etc)

Question 2

What is a compartment

Answer 2

A compartment is a collection of tissues into which a chemical distributes at approximately the same rate (NB blood is a considered a type of tissue)

Question 3

What is the single-compartment model (2)

Answer 3

1. Chemicals or drugs are distributed evenly and rapidly between blood and other tissues within the compartment
2. Tissues outside of this single compartment are not considered

Question 4

What is the two-compartment model (3)

Answer 4

1. Chemicals or drugs are distributed rapidly between blood and other tissues within one compartment
2. Chemicals or drugs are distributed more slowly to other tissues in a second compartment
3. Models can be generated considering every tissue as a separate compartment
   Here we will only consider a maximum of 2 compartments

Question 5

What is the importance of blood flow in distribution (2)

Answer 5

1. The rate of distribution to tissues is proportional to blood flow
2. Two compartments may be derived by “lumping” highly perfused tissues together into compartment 1 and considering slowly perfused tissues together in compartment 2

Question 6

What are the differences between single-compartment and two-compartment models? (5)

Answer 6

In the single-compartment model:

1. The dose (D) rapidly equilibrates through Volume (V)
2. Elimination from Compartment 1
3. Compartment 1 contains highly-perfused organs (liver, kidney, lungs) where excretion/elimination predominantly occurs

In the two-compartment model:

1. Dose (D) rapidly equilibrates through Volume (V) and slowly equilibrates through Volume (V2) back and forth
2. Elimination from Compartment 1

Question 7

What is the volume of distribution (V) (5)

Answer 7

1. Vd is a theoretical (or apparent) volume into which a drug distributes given its concentration measured in blood
2. It does not represent an actual physical volume.
3. For a given dose of drug we can measure the concentration in blood.
4. If the drug predominantly remains in the blood, blood concentration will be higher relative to a drug that is highly distributed into tissues.
5. V = Dose / Conc in blood

Question 8

What factors affect the volume of distribution (5)

Answer 8

1. V is a measure of the tendency of a drug to move out of the blood and into the tissues.
2. Drugs that are highly bound to tissue macromolecules or readily partition from water into phospholipid membranes can have very high V
3. Drugs that readily cross membranes but have little affinity for binding to biomolecules have intermediate V
4. Drugs that are highly bound to plasma proteins (albumin) or have difficulty passing through membranes tend to remain in blood and have low V
5. high distribution to muscle – may be reduced in elderly

Question 9

How does the binding of drugs affect distribution (5)

Answer 9

1. Free (unbound) drug can cross membrane and concentrations equilibrate.
2. Bound drug does not cross membrane.
3. In blood may bind to protein (albumin; a1 acid glycoprotein)
4. In tissue may bind to proteins, nucleic acids, lipids - more may be bound on one side or the other influencing V
5. Similarly ion trapping causes acidic drugs to accumulate in (relatively) basic environments and basic drugs to accumulate in acidic environments

Question 10

How is V normalised to body weight (3)

Answer 10

1. V is often reported in L - there is an assumption that the average adult weighs approx 70 kg.
2. Administering a fixed dose to individuals who are significantly smaller or larger can result in different blood concentrations. This may lead to an ineffective dose or a toxic dose being administered
3. V may be converted to L/kg (i.e. litres per kilogram body weight). This enables dosage to be adjusted for patients of different weights

Question 11

How can we achieve a blood concentration of 15 mg / L in a 50 kg patient. theophylline V = 35 L (assuming a 70kg average adult)

Answer 11

V theophylline = 35 L / 70 kg = 0.5 L/kg

(i) For 50 kg patient; V = 0.5 L/kg x 50 kg = 25 L

(Require conc of 15 mg/L)

V = dose / conc - rearrange to - V x conc = dose

25 L x 15 mg/L = 375mg

Question 12

How can we achieve a blood concentration of 15 mg / L in a 90 kg patient. theophylline V = 35 L (assuming a 70kg average adult)

Answer 12

V = 35L/70kg → 0.5L in 1kg

For a 90 kg patient; V = 0.5 L/kg x 90 kg = 45 L

V x conc = dose

45 L x 15 mg/L = 675 mg

Question 13

How do body types affect distribution (4)

Answer 13

1. Dose adjustments based on weights are reasonably accurate for normal body types
2. For obese patients a higher proportion of body weight is fat.
3. A water-soluble drug (such as digoxin) will not distribute well into fat and calculating V using body weight may lead to too high a dose being administered
4. Can use an “ideal weight” based on height to calculate dose rather than actual body weight

Question 14

What are Physiologically-Based Pharmacokinetic Models PBPK used for

Answer 14

predicting the concentration of drugs or other chemicals in organs

Question 15

What are the physiological and anatomical information used in physiologically-based Pharmacokinetic Models PBPK (3)

Answer 15

1. size/volume of organ
2. blood flow to the organ
3. capacity for metabolism/excretion etc

Question 16

What are Physiologically-Based Pharmacokinetic Models PBPK Adapted for (5)

Answer 16

1. Different routes of administration
2. Size (or age)
3. paediatrics
4. Disease states - polypharmacy
5. liver/kidney disease geriatrics

Question 17

What is the difference between a single-compartment and a two-compartment model? (simplified)

Answer 17

Drug is assumed not to equilibrate equally and rapidly through entire system – it distributes to one compartment more quickly than another

Question 18

“Lumping” is a process used to group what?

Answer 18

Compartments with rapid equilibration are lumped separately to those with slow equilibration – which relates to perfusion by blood

Question 19

Give an example of a highly perfused organ and a poorly perfused organ

Answer 19

High e.g. liver, kidney, brain

low = e.g. bone, adipose

Question 20

A patient receives a 20 mg dose of Drug Z. The concentration of Drug Z measured in her blood is 25 ug/L. What is the volume of distribution of this drug and what does this tell you about its tendency to move out of blood into tissues?

Answer 20

V = dose / Conc

V = 20 mg / 0.025 mg/L → 25ug/L = 0.025 mg/L

V = 800L – the drug has a large volume of distribution, therefore tends to move out of the blood into tissues – may be bound within tissues

Question 21

Drug M is available as its salt in 75% w/w preparation. The drug has a V recorded as 100 L (assuming a 70 kg average adult). If we wish to achieve a blood concentration of 20 mg/L in a 55 kg patient how much drug M should we administer?

Answer 21

V = 100L per 70 kg → 100/70 = 1.4 L/kg

For 55kg patient → V = 1.4 x 55 = 77 L

V = dose / conc

77 L = dose / 20 mg → Dose = 77 L x 20 mg/L = 1540mg = 1.54mg

Dose of salt = Dose of drug required/Salt factor

DoS = 1.54/0.75 = 2mg

Question 22

Complete the following:

1000ng = ……..mg

10mg = ………..mg

0.001g/mL = …..mg/L

1mg/L = ………..mg/mL

Answer 22

1000 ng = 1mg
10 mg = 10,000 mg
0.001g/mL = 1000 mg/L
1mg/L = 1 mg/mL