Elimination

Question 1

What is elimination?

Answer 1

Irreversible removal of drug from the body by all drug removal mechanisms

Question 2

What are the two main mechanisms under elimination?

Answer 2

1. Biotransformation (metabolism)
2. Excretion

Question 3

What is biotransformation (metabolism)?

Answer 3

Irreversible removal of drug by chemical conversion to metabolite

Metabolites can have active properties or be toxic

Biotransformation largely occurs in the liver, with some occurring in GI tract, lung, skin, and kidneys

Question 4

What is excretion?

Answer 4

Irreversible removal of intact (parent) drug from the body

Excretion is largely completed by the kidney, but can also occur in the liver, lung, saliva, and milk

Question 5

Are most drugs modified by one of the elimination mechanisms?

Answer 5

No, some are primarily eliminated via biotransformation, others by excretion, and the remaining by both biotransformation and excretion

Question 6

What is clearance in terms of elimination processes?

Answer 6

It is a measurement of the efficiency of mechanisms involved in drug removal (elimination) from the body

Question 7

What is the physiological definition of clearance?

Answer 7

Clearance is the volume of blood completely cleared of drug per unit time

Question 8

What is the general (mathematical) definition of clearance?

Answer 8

Clearance is a proportionality constant relating rate of elimination to the plasma concentration at a given point in time

Cl = rate of elimination/Cp, note Cl is a constant and any changes in plasma concentrations are adjusted for by shifts in the rate of elimination

Question 9

Refer to slide 5 for calculating systemic clearance from PK parameters

Question 10

Review slide 7 for an overview of oral clearance

Question 11

What are the principal elimination pathways for systemic clearance?

Answer 11

Hepatic and Renal

Question 12

What are the primary mechanisms for hepatic clearance?

Answer 12

Billary excretion (transporters)

Biotransformation (metabolism)
- Phase I (ex. P450)
- Phase II (conjugation enzymes)

Question 13

What are the primary mechanisms for renal clearance?

Answer 13

1. Glomerular filtration (GFR)
2. Tubular absorption and secretion

Question 14

Compare and Contrast

Systemic Clearance (Cls) vs. elimination rate constant (k)

Answer 14

Cls is a primary PK parameter (impacted by physiological state only)

k is a secondary PK parameter (impacted by primary Pk parameters)

k=Cls/Vd, note Cls and Vd are constants and do not change in linear PK systems

Question 15

What is extraction ratio (E) in terms of elimination?

Answer 15

This is the amount of drug that is removed from the blood by eliminating organs (liver and kidneys)

review slide 13 for equation for extraction ratio

Question 16

What are the two requirements for drug to be eliminated at eliminating organs?

Answer 16

1. Blood must deliver drug yo the elimnating organ (Q)
2. Eliminating organ must extract drug from blood (E)

Therefore, Clearance = Q (blood flow) x E (extraction ratio)

Question 17

What factors affect extraction?

Answer 17

1. Drug binding to/partitioning into blood cells
2. Drug binding to plasma proteins
3. Unbound drug diffusion into the hepatocyte
4. Unbound drug excretion
5. Unbound drug enzymatic biotransformation
6. Blood perfusion rate (Q) to the liver (elimination organ)

Question 18

What is the rate-limiting step in the elimination of high extraction ratio drugs?

Answer 18

High E (E is greater than 0.7)

Perfusion rate-limited (may need to adjust dose in patients with HF)

Question 19

What is the rate-limiting step in the elimination of low extraction ratio drugs?

Answer 19

Low E (E is less than 0.3)

Extraction is rate-limiting

Most drugs are low extraction ratio drugs

Question 20

Do the kidneys generally eliminate lipophilic drugs?

Answer 20

No, lipophillic drugs tend to be eliminated by the liver

The opposite applies to hydrophilic drugs, as they are eliminated by the kidneys