E1 L7: Bioavailability and Clearance 2

Question 1

What determines EH?

Answer 1

Intrinsic clearance = represents how good a compound is a substrate for different drug metabolizing enzymes
Large = good candidate = rapid elimination when seeing enzyme

Question 2

EH

Answer 2

Hepatic Extraction Ratio

Question 3

Max organ clearance values are equivalent to the

Answer 3

Blood flow to the organ

Question 4

Fraction of hepatic plasma flow from which drug is completely cleared

Answer 4

E

Question 5

CL =

Answer 5

QH * EH

Question 6

A fraction of drug eliminated by liver during single pass
Efficiency of liver to eliminate a drug
Values range from 0 (no metabolism) to 1 (complete metabolism)

Answer 6

Hepatic extraction ratio (EH)

Question 7

Volume of plasma from which a drug is completely eliminated (removed) by liver per unit time
Unit: volume/time e.g L/h, ml/min
Drug-dependent parameter
Values range from 0 to hepatic plasma flow (i.e. QH)

Answer 7

Hepatic Clearance (=QH * EH)

Question 8

High and Low EH drug values

Answer 8

High: >0.7
Low <0.3

Question 9

Low EH drugs

Answer 9

Theophylline
Warfarin

Question 10

High EH drug

Answer 10

Verapamil

Question 11

Low EH drug properties

Answer 11

High protein binding and/or low enzyme activity against a drug limit hepatic elimination

Question 12

High EH drug properties

Answer 12

These drugs are good substrates of drug-metabolizing enzymes, and protein binding does not limit metabolism

Question 13

Reflects the natural ability of the liver to metabolize a drug, independent of binding restrictions

Answer 13

CLint (intrinsic clearance)

Question 14

CLint properties

Answer 14

Property of a drug, just as VD, Kel and CL are
Unit: Volume/time
Values are greater than 0, but there is no upper limit
is Calculated from in vitro experiments (using liver tissues)

Question 15

Are the ones that are rapidly metabolized by the liver when the drugs are in unbound (free) form

Answer 15

Drugs of high CLint

Question 16

Are the ones that it takes longer to be metabolized even if the drugs are in unbound form

Answer 16

Drugs of small CLint

Question 17

Enzyme inhibitors (increase/decrease) CLint

Answer 17

Decrease

Question 18

Enzyme inducers (increase/decrease) CLint

Answer 18

Increase

Question 19

Low EH drugs: Increasing free fraction of drug would have - effects on its EH

Answer 19

Significant

Question 20

High EH drugs: Increasing free fraction of drug would have - effects on its Eh

Answer 20

Insignificant

Question 21

Unbound fraction

Answer 21

fu

Question 22

Well-stirred model equation

Answer 22

CLH = Fu * CLint

Question 22

Hepatic plasma flow

Answer 22

QH

Question 23

Well-stirred model: B-force

Answer 23

The more drug you have as free form, the better B force will be
B force is represented by the free fraction of the drug, and the intrinsic clearance of the drug

Question 24

Low EH drugs equation

Answer 24

CLH = fu * CLint

Question 25

High EH drugs equation

Answer 25

CLH = QH

Question 26

Factors affecting CLH

Answer 26

Hepatic Plasma Flow (QH):
Decreased by disease states like heart failure, liver disease, beta blockers
Increased by food
Hepatic enzyme activity (CLint)
Decreased by liver disease, dietary deficiencies, enzyme inhibiting drugs such as cimetidine
Increased by enzyme inducing drugs such as rifampin, and environmental pollutants including cigarettes
Binding to plasma proteins (fu)
Plasma proteins (albumin) are synthesized in the liver. Chronic liver diseases such as cirrhosis decrease circulating plasma protein concentrations

Question 27

PK parameter reflecting the rate of drug elimination from the body

Answer 27

CL

Question 28

PK parameter reflecting the rate of drug elimination from the liver

Answer 28

CLH

Question 29

Pk Parameter reflecting the rate of drug metabolism by hepatic drug-metabolizing enzymes

Answer 29

CLint

Question 30

Q: Drug A is eliminated 100% by hepatic metabolism. Drug A’s CL is 100ml/min
T/F:
1: Drug A is a high EH drug
2. Drug A’s fe = 0
3. Rifampin will likely increase CLint of drug A

Answer 30

1. False (CLH/QH = 100/700 = 0.14)
2. True
3. True

Question 31

Q: T/F: Rifampin will likely increase CLH of of Low EH drugs

Answer 31

True (CLint = CLH)

Question 32

Q: T/F: Rifampin will likely increase CL of low EH drugs

Answer 32

True (CL = CLH)

Question 33

Q: T/F: B-blockers will likely decrease CL of Low EH drugs

Answer 33

False - Decreased QH

Question 34

Q: Drug B is eliminated 100% by hepatic metabolism. Drug B’s CL is 600 mL/min
T/F:
1. Drug B is a high EH drug
2. Drug B’s fe = 0
3: Rifampin will likely increase CLint of Drug B

Answer 34

1. True (600/700=0.86)
2. True (fe is 0, drug is eliminated by hepatic 100% - no parent drug in urine)
3. True (CL reflects how fast drug metabolizes drug B, it will go up)

Question 35

Q: T/F: Rifampin will likely increase CLH of High EH drug

Answer 35

False: CLH = QH

Question 36

Q: T/F: Rifampin will likely increase CL of High EH drug

Answer 36

False (CL = CLH)

Question 37

Q: T/F: B-blockers will likely decrease CL of Drug B

Answer 37

True (Decreased QH = true)