Rates and Orders of Reactions: Pharmacokinetic Models II

Question 1

Answer True or False.

In One-Compartment model IV bolus administration:

a. Elimination follows first order kinetics.
b. The entire dose enters the body instantanoeusly
c. The rate of absorption is negligible in calculations
d. The entire body acts as a single compartment
e. The drug rapidly equilibrates with all the tissues in the body

Answer 1

a. True
b. True
c. True
d. True
e. True

Question 2

About IV bolus administration. Provide the formulas for the following:

1. Final concentration (C)
2. Half-life (t1/2)
3. Volume of distribution (Vd)
4. Clearance (CL)
5. AUC

Answer 2

1. InC = -kt + InCo
2. t1/2 = 0.693/k
3. Vd = Dose/Co
4. CL = Ke x Vd
5. AUC = Co/Ke

Question 3

Answer True or False.

In One-Compartment model IV continuous infusion administration:
a. Drug is introduced into body at constant rate over a period of time.
b. Ro is assumed as constant (zero order) rate of infusion or absorption
c. Elimination is assumed to be following First order kinetics
d. If the intravenous infusion is discontinued, the plasma drug concentration declines by a first order process
e. As the drug is infused, the plasma drug concentration increases to a plateau, or steady-state concentration (Css)

Answer 3

a. True
b. True
c. True
d. True
e. True

Question 4

Css is expressed as

Answer 4

Css = Ro/CT

Css = Ro/(ke x Vd)

Question 5

In One-Compartment model IV continuous infusion administration, the formula relating C to Css is

Answer 5

C = Css [1-e ^ (-Ke x t)]

Question 6

Answer True or False.

In One-Compartment model Extravascular administration:
a. The drug is generally absorbed by first-order kinetics
b. Elimination of the drug also follows the principles of first-order kinetics
c. In normal cases Absorption rate constant&raquo_space; Elimination rate
constant
d. If Elimination rate constant&raquo_space; Absorption rate constant, then the drugs are said to be following Flip-Flop model

Answer 6

a. True
b. True
c. True
d. True

Question 7

Non-Compartmental Analysis is also called ________, and it describes drug pharmacokinetics using ________ and ________ parameters.

Answer 7

Model independent method
Time and Concetartion parameters

Question 8

Non-compartmental analysis can be applied to any compartment model if the drugs or metabolites follow non-linear kinetics.

True or false?

Answer 8

False.
The compartmental model has to follow linear kinetics

Question 9

What is MRT?

Answer 9

Mean residence time. Also called Mean sojourn time, is the average time for the drug molecules to reside in the body.

MRT = AUMC/AUC
MRT(iv) = 1/Ke

Question 10

What is MAT?

Answer 10

Mean absorption time (MAT) is the difference between MRTev and MRTIV after an extravascular route is used.

MAT = MRT(ev) - MRT(iv)

Question 11

What is clearance?

Answer 11

Clearance is the volume of plasma cleared of drug per unit time.
It may be calculated without consideration of the compartment mode

Question 12

What is non-linear pharmacokinetics?

Answer 12

It is also known as capacity-limited, dose-dependent, or saturation pharmacokinetics.

At lower dose, drug shows first order kinetics but at higher dose, it shows zero order due to saturation. For this reason, it is also known as Mixed order Kinetics.

It may result from the saturation of an enzyme- or carrier-mediated system.

Question 13

Mention 4 characteristsics of non-linear pharmacokinetics.

Answer 13

i. The AUC is not proportional to the dose
ii. The amount of drug excreted in the urine is not proportional to the dose
iii. The elimination half-life may increase at high doses
iv. The ratio of metabolites formed changes with increased dose

Question 14

How do you test for non-linearity?

Answer 14

i. Determine Css at different doses and if it is proportional to the doses then it is linear pharmacokinetics else it is nonlinear pharmacokinetics

ii. Determine some important pharmacokinetic parameters such as: fractional bioavailability F, t1/2, total clearance at different doses.
Changes in parameters which are usually constant, means non-linear pharmacokinetics

Question 15

Discuss the causes of non-linearity under absorption, distribution, metabolism and excretion

Answer 15

1. Drug absorption:
   - When the absorption is solubility or dissolution rate limited eg., Griseofulvin
   - When absorption involves carrier mediated transport, saturation at higher dose result in nonlinearity eg., Ribofalvin
   - When pre systemic gut wall or hepatic metabolism attains saturation eg., Propranolol
2. Distribution:
   - Saturation of plasma protein binding
   - Saturation of tissue binding sites
3. Drug metabolism:
   - Capacity limited metabolism due to the enzyme or cofactor saturation
   - Enzyme induction
   - Hepatotoxicity, change in hepatic blood flow and inhibitory effects of metabolites on enzyme
4. Excretion
   - Active tubular secretion; decreases renal clearance
   - Active tubular reabsorption; Increases renal clearance
   - Forced diuresis, change in urine pH, nephrotoxicity