Exam 1 Bioavailability and Clearance 2

Question 1

What is considered to be a significant change?

Answer 1

when the starting value is small so there is at least a two fold difference from before and after

Question 2

What is the extraction ratio (E)?

Answer 2

1. a fraction of drug eliminated by a drug eliminating organ during single pass
2. efficiency of a drug eliminating organ to eliminate a drug
3. values range from 0 to 1
4. drug dependent parameter → like kel, Vd, and CL that are all drug dependent

Question 3

A larger extraction ratio (E value) means what?

Answer 3

that the drug gets eliminated faster than another drug with a smaller E value

Question 4

What is CA and CV and how does that affect the extraction ratio?

Answer 4

CA is the drug concentration in the artery and CV is the drug concentration in the vein → the same amount of blood volume is going in and out but Ca > Cv

Question 5

What is Q and E in terms of the extraction ratio?

Answer 5

Q is the plasma flow to the organ while E is the fraction of plasma flow from which the drug is completely cleared

Question 6

What is the equation for organ CL?

Answer 6

organ CL = Q*E (where Q is the plasma flow to the organ and E is the fraction of plasma flow from which the drug is completely cleared (top part of arrow))

Question 7

What is organ clearance?

Answer 7

1. volume of plasma from which a drug is completely eliminated (removed) by a drug eliminating organ per unit time (=Q*E)
2. units: volume/time such as L/hr or mL/min
3. values range from 0 to plasma flow to the organ (Q)
4. drug dependent parameter

Question 8

If E=0.3 and Q=1 L/min, then what is organ CL?

Answer 8

CL = QE = 10.3 = 0.3 L/min

Question 9

What is hepatic extraction ratio (Eh)?

Answer 9

1. fraction of drug eliminated by liver during single pass
2. efficiency of liver to eliminate a drug
3. values range from 0 (no metabolism) to 1 (complete metabolism)
4. is the top part of the arrow like E

Question 10

What is hepatic clearance?

Answer 10

1. equal to Qh*Eh
2. volume of plasma from which a drug is completely eliminated (removed) by liver per unit time
3. values range from 0 to hepatic plasma flow (Qh)

Question 11

What is hepatic plasma flow (Qh)?

Answer 11

0.7 L/min (physiological value)

Question 12

What type of property is the extraction ratio (Eh)?

Answer 12

the extraction ratio is a property of the drug

Question 13

What are the different Eh values for different drugs?

Answer 13

high Eh drugs have Eh > 0.7 while low Eh drugs have Eh < 0.3

Question 14

What happens if Eh is approximately 1?

Answer 14

CLh approaches Qh (the hepatic clearance would approach the hepatic plasma flow)

Question 15

Drug X is mainly eliminated by hepatic metabolism. when drug X’s systemic clearance is 0.6 L/min, what is Eh? (fe =0, CL = CLh)

Answer 15

Eh = CLh / Qh = 0.6/0.7 = 0.86 → is a high Eh drug (since greater than 0.7)

Question 16

What are the two low Eh drugs we should know?

Answer 16

theophylline and warfarin

Question 17

What is the high Eh drug we should know?

Answer 17

verapamil

Question 18

What is some important info to know about low Eh drugs?

Answer 18

1. warfarin → protein binding of 99% (high)
2. theophylline → protein binding of 56% (intermediate)
3. high protein binding and low enzyme activity against a drug limit hepatic elimination

Question 19

What is some important info to know about high Eh drugs?

Answer 19

1. verapamil → protein binding is 90% (high)

2. these drugs are good substrates of drug metabolizing enzymes and protein binding does not limit metabolism

Question 20

How is intrinsic clearance (CLint) calculated?

Answer 20

experimentally

Question 21

What is intrinsic clearance?

Answer 21

1. reflects the natural ability of the liver to metabolize a drug, independent of binding restrictions
2. property of a drug (like kel, Vd, and CL)
3. units of volume/time like mL/min or L/hr
4. values are greater than 0 but has no upper limit
5. drugs with large CLint are the ones that are rapidly metabolized by the liver when the drugs are in free form
6. drugs with small CLint are the ones that takes longer to be metabolized even if drugs are in unbound/free form
7. calculated from in vitro experiments using liver tissues (ratio Vmax/Km)

Question 22

What is the equation for rate of elimination?

Answer 22

-CL*Cp

Question 23

What is the equation for the rate of metabolism?

Answer 23

CLm*Cu (Cu is unbound drug concentration)

Question 24

What is the equation for intrinsic clearance (CLint)?

Answer 24

CLint = Vmax / Km (in which CLint is the largest metabolic clearance value possible)

Question 25

How do enzyme inducers affect CLint?

Answer 25

known to induce protein expression of drug metabolizing enzymes (examples include phenobarbital and rifampin) → increase the CLint of interacting drugs

Question 26

How do enzyme inhibitors affect CLint?

Answer 26

many drugs are known to inhibit the function of drug metabolizing enzymes (such as erythromycin and cimetidine) → decrease the CLint of interacting drugs

Question 27

The CLint of a drug reflects what?

Answer 27

it reflects how good a substrate a drug is to drug metabolizing enzymes → higher CLint means good substrate and lower CLint means poor substrate

Question 28

Increasing the free fraction of a low Eh drug has what effect on its Eh?

Answer 28

increasing free fraction of low Eh drug would have significant effect on its Eh

Question 29

Increasing the free fraction of a high Eh drug has what effect on its Eh?

Answer 29

increasing free fraction of high Eh drug would have insignificant effects on its Eh (since it is already high)

Question 30

What is the well stirred model?

Answer 30

A is the hepatic plasma flow and B is CL for a low Eh drug → A >> B so CLh = fu*CLint for a high Eh drug → A << B so CLh = Qh (which is 0.7 L/min)

Question 31

What are the three factors affecting CLh?

Answer 31

1. hepatic plasma flow (Qh) 2. hepatic enzyme activity (CLint) 3. binding to plasma proteins (fu)

Question 32

How is hepatic plasma flow affected?

Answer 32

1. decreased by disease states such as heart failure, liver disease and drugs such as propranolol (is a beta blocker) 2. increased by food

Question 33

How is hepatic enzyme activity (CLint) affected?

Answer 33

1. decreased by liver disease, dietary deficiencies, enzyme inhibiting drugs such as cimetidine 2. increased by enzyme inducing drugs such as phenobarbital, rifampin, and environmental pollutants including polycyclic hydrocarbons (in cigarettes)

Question 34

How is binding to plasma proteins (fu) affected?

Answer 34

1. plasma proteins like albumin are synthesized in the liver → chronic liver diseases such as cirrhosis decrease circulating plasma protein concentrations 2. changes in plasma binding can result from displacement of drugs from plasma proteins by other drugs with higher affinity for the same protein binding site (ex. aspirin displaces warfarin from albumin) → more free drug

Question 35

How is CLh affected for low Eh drugs?

Answer 35

CLh is not affected for low Eh drugs

Question 36

How is CLh affected for high Eh drugs?

Answer 36

change in CLh is proportional to change in Qh for high Eh drugs

Question 37

How does enzyme activity (CLint) affect low Eh drugs?

Answer 37

changes in enzyme activity (CLint) proportionally influences CLh

Question 38

How does enzyme activity (CLint) affect high Eh drugs?

Answer 38

changes in enzyme activity (CLint) do not affect CLh for high Eh drugs

Question 39

How does fraction unbound (fu) affect low Eh drugs?

Answer 39

change in CLh is proportional to change in fu for low Eh drugs

Question 40

How does unbound fraction (fu) affect high Eh drugs?

Answer 40

changes in fu do not affect CLh for high Eh drugs

Question 41

What is the summary for low Eh drugs?

Answer 41

CLh is rate limited by concentration of unbound drug that enters hepatocytes and metabolic activity → CLh is therefore affected only by changes in CLint and fu

Question 42

What is the summary for high Eh drugs?

Answer 42

CLh is rate limited by rate of drug presentation to liver → therefore, CLh is affected only by changes in Qh

Question 43

What are the two approaches to study factors affecting CLh?

Answer 43

1. in vitro → using perfused animal liver in which perfusion rate (Qh) and protein binding (fu) can be manipulated 2. in vivo → examine PK parameters in drug-drug interaction studies

Question 44

Given a graph, how do you determine the low Eh drugs and high Eh drugs?

Answer 44

top of the graph is high Eh drugs and towards the bottom are the low Eh drugs

Question 45

What are some other examples of low and high Eh drugs?

Answer 45

high Eh → propranolol, lidocaine low Eh → diazepam (limited by protein binding), phenytoin, tolbutamide (limited by both protein binding and enzyme activity), antipyrine

Question 46

If lidocaine's fe=0, then what is the relationship between CL and CLh?

Answer 46

CL = CLh

Question 47

Which of Qh, fu, or CLint does a beta blocker influence?

Answer 47

Qh → beta blocker like propranolol is a high Eh drug so CLh = Qh and it would decrease Qh

Question 48

What would the use of beta blockers do to the CLh of antipyrine (a low Eh drug)?

Answer 48

nothing → beta blockers are high Eh drugs and low Eh drugs are given by CLh = fu*CLint

Question 49

For warfarin, which of Qh, fu, or CLint does rifampin influence and in which direction?

Answer 49

increase CLint → warfarin is a low Eh drug so (CLh = fu*CLint) and enzyme inducers only affect CLint proportionally

Question 50

For warfarin, its fe =0. What is the relationship between CL and CLh?

Answer 50

CL = CLh

Question 51

Assuming that rifampin does not affect Vd of warfarin, what is the effect of rifampin on warfarin t1/2?

Answer 51

decreases t1/2 → rifampin is an inducer so it would increase CLint and CL = kel*vd so if vd remained the same, then kel would also increase and if kel increases, t1/2 would decrease since kel = 0.693/half life (inverse relationship)

Question 52

If a drug is 100% metabolized, (no renal excretion), then what happens?

Answer 52

fe=0 → CL = CLh (ALWAYS)