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Pharmacokinetics > Exam 1 Bioavailability and Clearance 2 > Flashcards

Exam 1 Bioavailability and Clearance 2 Flashcards

1
Q

What is considered to be a significant change?

A

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

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2
Q

What is the extraction ratio (E)?

A
  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
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3
Q

A larger extraction ratio (E value) means what?

A

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

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4
Q

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

A

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

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5
Q

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

A

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

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6
Q

What is the equation for organ CL?

A

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))

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7
Q

What is organ clearance?

A
  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
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8
Q

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

A

CL = QE = 10.3 = 0.3 L/min

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9
Q

What is hepatic extraction ratio (Eh)?

A
  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
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10
Q

What is hepatic clearance?

A
  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)
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11
Q

What is hepatic plasma flow (Qh)?

A

0.7 L/min (physiological value)

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12
Q

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

A

the extraction ratio is a property of the drug

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13
Q

What are the different Eh values for different drugs?

A

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

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14
Q

What happens if Eh is approximately 1?

A

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

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15
Q

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)

A

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

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16
Q

What are the two low Eh drugs we should know?

A

theophylline and warfarin

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17
Q

What is the high Eh drug we should know?

A

verapamil

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18
Q

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

A
  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
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19
Q

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

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

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

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20
Q

How is intrinsic clearance (CLint) calculated?

A

experimentally

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21
Q

What is intrinsic clearance?

A
  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)
22
Q

What is the equation for rate of elimination?

A

-CL*Cp

23
Q

What is the equation for the rate of metabolism?

A

CLm*Cu (Cu is unbound drug concentration)

24
Q

What is the equation for intrinsic clearance (CLint)?

A

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

25
Q

How do enzyme inducers affect CLint?

A

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

26
Q

How do enzyme inhibitors affect CLint?

A

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

27
Q

The CLint of a drug reflects what?

A

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

28
Q

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

A

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

29
Q

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

A

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

30
Q

What is the well stirred model?

A

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

31
Q

What are the three factors affecting CLh?

A
  1. hepatic plasma flow (Qh)
  2. hepatic enzyme activity (CLint)
  3. binding to plasma proteins (fu)
32
Q

How is hepatic plasma flow affected?

A
  1. decreased by disease states such as heart failure, liver disease and drugs such as propranolol (is a beta blocker)
  2. increased by food
33
Q

How is hepatic enzyme activity (CLint) affected?

A
  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)
34
Q

How is binding to plasma proteins (fu) affected?

A
  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
35
Q

How is CLh affected for low Eh drugs?

A

CLh is not affected for low Eh drugs

36
Q

How is CLh affected for high Eh drugs?

A

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

37
Q

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

A

changes in enzyme activity (CLint) proportionally influences CLh

38
Q

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

A

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

39
Q

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

A

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

40
Q

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

A

changes in fu do not affect CLh for high Eh drugs

41
Q

What is the summary for low Eh drugs?

A

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

42
Q

What is the summary for high Eh drugs?

A

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

43
Q

What are the two approaches to study factors affecting CLh?

A
  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
44
Q

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

A

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

45
Q

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

A

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

46
Q

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

A

CL = CLh

47
Q

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

A

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

48
Q

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

A

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

49
Q

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

A

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

50
Q

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

A

CL = CLh

51
Q

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

A

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)

52
Q

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

A

fe=0 → CL = CLh (ALWAYS)

Pharmacokinetics (14 decks)

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