Rates and Orders of Reactions: Pharmacokinetic Models

Question 1

What is a model?

Answer 1

It is a mathematical description of a biological system.

Question 2

Why do we use models?

Answer 2

They a provide concise means of expressing quantitatively, the time course of drug(s) throughout the body and compute meaningful pharmacokinetics parameters

Question 3

What are the types of models?

Answer 3

i. Compartment model
ii. Non-compartment model
iii. Physiological model

Question 4

What is a compartment?

Answer 4

It is a group of tissues with similar perfusion and drug affinity.

Question 5

What is the formula for plasma drug concentration?

Answer 5

Cp = D/Vd

Question 6

What is apparent volume of distribution?

Answer 6

It is the hypothetical volume of body fluid in which a drug is dissolved.

Question 7

What are the assumptions of the One-Compartment Model?

Answer 7

i. Instant and homogenous distribution
ii. Equilibrium between blood and other compartments
iii. Level of drug in plasma is proportional but not necessarily equal to that found in any of the tissues into which the drug is distributed
iv. Conc of drug at site of action is in equilibrium with plasma drug conc so a correlation exists between pharmacological response and plasma conc.

Question 8

What are the assumptions of the Two-Compartment Model?

Answer 8

i. Distribution requires measurable time for pseudo-equilibrium
ii. Drug enters and leaves the body through the central compartment only
iii. It is not a straight-line graph but a crve that doesn’t decline linearly.
iv. k, k12 and k21 are firts-order rate constants
v. At t= 0, concentration in peripheral compartment is 0.

Question 9

What is the central compartment?

Answer 9

The blood and highly perfused tissues and organs such as the brain, liver, heart, muscle, bone marrow etc.

Question 10

What is the tissue/peripheral compartment?

Answer 10

The poorly perfused tissues which take longer time to equilibrate e.g bones, nails, hair, teeth, cartilage, tendons and ligaments

Question 11

How do you calculate the apparent volume of distribution in plasma (central conpartment) (Vp) in a Two-Compartment model?

Answer 11

Vp = D/(A+B)

where
D = dose of drug
A = Intercept of first phase
B = intercept of second phase

Question 12

How do you calculate the apparent volume of distribution in tissue compartment (Vt) in a Two-compartment model?

Answer 12

Vt = Vp(k12/k21)

Question 13

How do you calculate the apparent volume of distribution at steady state (Vdss) in a Two-Compartment model?

Answer 13

Vdss = Vp(1 + (k12/k21))

Question 14

How do you calculate the apparent volume of distribution by AUC (Vdβ) in a Two-Compartment model?

Answer 14

Vdβ = CL/β

Vdβ = (Vp x ke)/β

β = rate constant in terminal phase
ke = elimination constant
Vp = Apparent volume of distribution in plasma

Question 15

How do you calculate the extrapolated volume of distribution in a Two-Compartment Model?

Answer 15

Vd.exp = Vp (ɑ - β/ K21 – β)

Question 16

How do you calculate clearance from central compartment based on elimination constant?

Answer 16

CT = Vp x ke

Question 17

How are two-compartment rate constants ɑ and β determined?

Answer 17

β
- calculated from slope of beta-phase
- calculated from half-life of the drug determined from beta-phase

ɑ
-Can be determined from the Conc-time graph with the residual method

Question 18

What are the assumptions of the three-compartment model?

Answer 18

i. Drug enters into and leaves the body only through the central compartment
ii. K, K12 and K21, K13 and K31 are first order rate constants
iii. At time zero (t0), concentration in the tissue and deep tissue compartment is 0

Question 19

What are the 3 phases of drug distribution in the three-compartment model?

Answer 19

i. First, rapid distribution to central compartment
ii. Second, slow distribution to tissue compartment
iii. Third, much slower distribution from central compartment to deep tissue compartment

Question 20

Insulin given by IV follows the three-compartment model.

True or False?

Answer 20

True