Lecture 5- Clearance Concepts

Question 1

Describe the processes of elimination and where they occur.

Answer 1

Elimination occurs by excretion and metabolism.
Excretion: urine (kidney), bile (biliary system), breath (lung)
Metabolism: liver, kidney, lung, blood, gastrointestinal wall.

Question 2

What are the different descriptions of clerarance?

Answer 2

By organ: hepatic clearance, renal clearance, pulmonary clearance
By process: metabolic clearance, excretory clearance (CLexcretion).
Renal versus others:
- Renal clearance, extrarenal clearance
By site of measurement:
- hepatic metabolic plasma clearance
- renal excretory plasma clearance

Question 3

Name the two definitions of CLb

Answer 3

First definition :
rate of elimination (mg/min) = CLb.Cb = CL.C = CLu.Cu

Second definition:
CLb (L/min) = Q (L/min) x E

Question 4

What is the rationale behind the first definition?

Answer 4

• In linear PK, CLb, CL and CLu are constant.

Question 5

What is the rationale behind the second definition?

Answer 5

rate of elimination (extraction) in an organ = Q (Ca-Cv)
CLb= rate of elimination/Cb
= Q(Ca-Cv)/Ca
= Q x E , as E = (Ca-Cv)/Ca

Question 6

What is an alternative, more common way to calculate rate of elimination?

Answer 6

CL x C

Question 7

What is the unit for rate of elimination?

Answer 7

mg/min

Question 8

How can you calculate clearance?

Answer 8

CL =  rate of elimination/C 
CL = Q x E 
CL = CLb/(C/Cb)
CL= V x k (fractional rate constant)

Question 9

Why do drugs have different E?

Answer 9

they may be good/bad substrates of enzymes or transporters.

Question 10

Does low E mean that the pathway of elimination is not major nor important?

Answer 10

No, especially if drug is only metabolised by one enzyme in the pathway, even if it has low E, the pathway is important.

Question 11

What are the boundaries of E, and what happens when E is large?

Answer 11

E takes the form of a ratio from 0 to 1.
When E is large, elimination efficiency is high:
1. Cout ~0 (output concentration is very low)
2. E will approach 1
3. Organ blood clearance becomes limited by blood flow.

Question 12

What happens when E is small (<0.1)?

Answer 12

1. Drug is not extracted efficiently by the organ.
2. Cout~Cin (output and input concentration are similar)
3. (Cin - Cout) / Cin gives a small number
4. Organ blood clearance is only a small fraction of blood flow, largely independent blood flow.

Question 13

What is the maximum value that organ blood clearance can take, and what is the term that is used to classify it?

Answer 13

Maximum value is blood flow (Q), approximately 1.35L/min from liver, term is known as flow-limited clearance.

Question 14

What is the concept of additivity of clearance?

Answer 14

• total clearance is a sum of the clearances in all the other organs.
• CL= CL(hepatic) + CL (renal) + CL (others_
• clearance of drug by one organ adds to the clearance of another (except for pulmonary clearance).

Question 15

What does k stand for and how to calculate k?

Answer 15

k- fractional rate of drug elimination

k = CL/V

Question 16

how is k, CL and V associated with t1/2?

Answer 16

k = 0.693/t1/2
t1/2 = 0.693V/CL
As CL increases, half-life decreases fora given V.
As V increases, half-life increases for a given CL.

Question 17

T/F: V and CL are dependent on one another.

Answer 17

False, both terms are independent of one another.
V is related to physicochemical properties of drug, plasma protein and tissue binding.
CL is related to capacity and ability of clearing organs to remove drugs.

Question 18

What is the clinical effect of CL on half-life?

Answer 18

In increasing order of half-life, decreasing clearance value:
active secretion < filtration< reabsorption