ADME (Lectures 2 and 3)

Question 1

1. Explain the difference between first-order, zero-order, and dose-dependent kinetics of drug elimination

Answer 1

a. First-order: The elimination rate of the drug is a constant fraction of the drug remaining in the body per unit time; there is an elimination rate constant
b. Zero-order: displayed by drugs that are eliminated primarily by metabolism; when metabolic pathways are saturated, metabolism occurs at a fixed rate (d/n change in proportion to [drug]); a fixed amount of drug is metabolized per unit time
c. Dose-dependent: when a drug’s elimination is mediated predominantly by metabolism, its elimination will tend to follow first-order kinetics when concentrations are well below the KM of the metabolic enzymes, but will follow zero-order kinetics at doses that greatly exceed the KM of the metabolic enzymes

Question 2

Name three dose-dependent drugs

Answer 2

Phenytoin, ethanol, aspirin

Question 3

What are the two primary pharmacokinetic parameters?

Answer 3

Clearance and Volume of distribution

Question 4

How would increasing hepatic blood flow affect clearance?

Answer 4

Increased hepatic blood flow would increase clearance

Question 5

How would increased protein binding affect clearance?

Answer 5

Increased protein binding would decrease clearance

Question 6

What would decrease protein binding?

Answer 6

Pregnancy
Malnutrition
Burns
Liver disease
Kidney disease
Cystic fibrosis

Question 7

Which drugs bind tightly to albumin?

Answer 7

Warfarin
Sulfa’s
Phenytoin

Question 8

What two systems comprise intrinsic clearance?

Answer 8

Hepatocellular metabolism

Biliary excretion

Question 9

What is restrictive hepatic clearance?

Answer 9

Clearance that is not dependent on hepatic blood flow. Drugs that exhibit such clearance have a low first-pass effect, as these are highly protein-bound drugs. (Metabolic) Capacity-limited clearance.

Ex. phenytoin and warfarin

Question 10

What is non-restrictive hepatic clearance?

Answer 10

Clearance that is dependent on hepatic blood flow. Huge first-pass effect, low bioavailability following liver.

Ex. lidocaine, propranolol

Question 11

What would most significantly affect restrictive hepatic clearance?

Answer 11

Changes in drug metabolism or biliary excretion (aka, intrinsic clearance)

Question 12

What would most significantly affect non-restrictive hepatic clearance?

Answer 12

Changes in hepatic blood flow

Question 13

Where are Type I drug receptors?

Answer 13

On the plasma membrane

Question 14

Where are Type II drug receptors?

Answer 14

In the cytoplasm

Question 15

Where are Type III drug receptors?

Answer 15

In the nucleus

Question 16

Explain a one compartment model

Answer 16

A rapid equilibrium is achieved between plasma and tissue distribution following drug administration. Plasma concentration-time profile declines mono-exponentially

Question 17

Explain a two-compartment model

Answer 17

A rapid distribution to a central compartment (plasma) is followed by slow distribution to other tissues/binding sites (second compartment). This results in bi-exponential plasma concentration-time profile