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Pharmacokinetics > Exam 2 Metabolite Kinetics > Flashcards

Exam 2 Metabolite Kinetics Flashcards

1
Q

How are metabolites excreted?

A

biliary excretion

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2
Q

How do metabolites contribute to drug response?

A

metabolites can affect PK of parent drugs and alter pharmacologic response to the parent drug → example is acetaminophen in which NAPQI is its toxic metabolite

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3
Q

What are two compounds and their metabolites?

A
  1. codeine → morphine (analgesic effect coming from codeine is actually from the active metabolite morphine)
  2. zidovudine → zidovudine triphosphate (anti-viral agent)
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4
Q

What are prodrugs?

A

molecules with little to no pharmacologic activity that are converted to the active drug in vivo by enzymatic or chemical reactions

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5
Q

What is an example of a prodrug?

A

irinotecan (inactive prodrug that is an anti-cancer agent that cannot kill cancer cells by itself) → SN-38 (active by carboxyesterase that is abundant in the body that takes away its ester group) → SN-38 glucoronide (inactive by UGT that is then biliary excreted)

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6
Q

What is the rate limiting step?

A
  1. most effects of metabolites are concentration dependent
  2. need to understand the formation and elimination kinetics of metabolites
  3. rate limiting step (the slowest step) defines PK profile of metabolite
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7
Q

What is the equation for rate limiting step?

A

dA/dt = kfA - kmAm (rate of metabolite formation - rate of metabolite elimination)

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8
Q

If you pick 5 apples/hour and your sister has the capacity to eat 10 apples/hour, how many apples would she eat?

A

5 apples/hour (true rate and apparent rate is different)

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9
Q

What is the true rate compared to the apparent rate?

A

true rate → the true capacity of the person eating apples

apparent rate → what you end up seeing

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10
Q

If you pick 5 apples/hour and your brother has the capacity to eat 1 apple/hour, how many apples would he eat?

A

1 apple/hour (true rate and apparent rate are the same)

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11
Q

What is the apparent rate?

A

the metabolite formation rate

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12
Q

What is the true rate?

A

the metabolite elimination rate

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13
Q

What happens when apparent rate is slower than true rate?

A

the apparent rate of her eating apples is determined by “apple picking” rate (the slower rate) → the metabolite elimination rate is greater than the metabolite formation rate

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14
Q

What happens when metabolite elimination rate is greater than metabolite formation rate?

A

parent drug to metabolite is slow but metabolite to elimination is fast → the apparent elimination rate of metabolite is determined by metabolite formation rate (or parent drug disappearance rate is fe=0) → half life of parent drug and metabolite are equal (will have parallel slopes)

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15
Q

What happens when the true rate and apparent rate are equal?

A

the apparent rate of him eating apples is determined by his true capability to eat the apple → apparent elimination of metabolite is determined by true metabolite elimination rate → parent drug is rapidly converted to its metabolite but the metabolite gets eliminated slowly → the half life of parent drug is less than half life of metabolite

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16
Q

How is metabolite elimination rate accurately estimated?

A

metabolites should be administered

17
Q

In many cases, when is information on metabolite kinetics obtained?

A

after administration of parent drug → measure parent drug to estimate metabolite data

18
Q

If metabolite formation is slower than elimination, what is the rate limiting step that determines metabolite amount in the body?

A

formation of the metabolite → parent drug and metabolite have the same half life

19
Q

If elimination rate is faster than metabolism rate, what is the apparent half life of the parent drug and the metabolite?

A

the same → but the true half life of the metabolite would be smaller

20
Q

When metabolism rate is greater than elimination rate, what is the rate limiting step that determines metabolite amount in the body?

A

elimination of metabolites → parent half life is shorter than metabolite half life

21
Q

If metabolism rate is faster than elimination rate, what is the apparent half life of the parent drug and the metabolite?

A

apparent half life of parent drug is smaller than apparent half life of metabolite → but true half life of metabolite is equal to the apparent half life of metabolite

22
Q

What is the typical pattern for most drugs?

A
  1. K &laquo_space;Km (metabolite formation is slower than elimination)
  2. metabolite elimination is formation rate limited
  3. true half life of metabolite is shorter than half life of parent drug
  4. apparent half life of metabolite is equal to half life of parent drug
23
Q

What is the typical pattern for most prodrugs?

A
  1. K&raquo_space; Km (metabolite formation is faster than elimination)
  2. apparent metabolite elimination is metabolite elimination rate limited
  3. both the apparent and true half life of metabolite is longer than half life of parent drug
24
Q

What is an example of formation limited?

A
  1. tolbutamide → hydroxytolbutamide (metabolite) by CYP2C9
  2. plasma concentrations of tolbutamide and hydroxytolbutamide after an IV bolus dose of 1 g → slopes are parallel to each other
  3. similar apparent half life between parent drug and metabolite → metabolite elimination is formation rate limited
25
Q

Tolbutamide is a low Eh drug and its fe=0. What would happen to half life of tolbutamide when it is combined with rifampin, an inducer of CYP2C9 expression?

A

decreased half life → inducers increase CL and CL = k*V and half life = 0.693/k

26
Q

What would happen to half life of hydroxytolbutamide when tolbutamide is combined with rifampin, an inducer of CYP2C9 expression?

A

decreased half life (since it is formation rate limited, parent and metabolite have same apparent half life)

27
Q

What is an example of elimination-limited?

A

methylprednisolone hemisuccinate (not good water solubility for methylprednisolone alone but ester group increases solubility) → methylprednisolone

28
Q

What is time to reach steady state for formation rate limited?

A
  1. time to reach steady state is determined by half life

2. time to reach steady state for metabolite is the same as that of parent drug (since they have the same half life)

29
Q

What is time to reach steady state for elimination rate limited?

A
  1. time to reach steady state is determined by half life
  2. time to reach steady state for metabolite is longer than that of parent drug (since half life is longer for metabolite)
30
Q

What is the first pass effect with active metabolites?

A

drugs that experience significant first pass effect (high Eh) show high metabolite to parent drug concentration ratio after oral administration as compared to IV (example is naphthoxylactic acid) → if give drug as IV, 20% of drug goes to the liver compared to orally in which 100% of drug goes to liver

31
Q

What happens when drugs of high Eh are administered and the metabolites are inactive?

A
  1. concentrations of parent drug correspond to pharmacological effect
  2. IV administration typically leads to faster drug response
  3. low F of the drug requires higher oral doses
  4. example) labetalol → labetalol glucoronide (inactive)
32
Q

What happens when prodrugs of high Eh are administered?

A
  1. a shorter onset and more intense response may occur after oral administration than IV
  2. low F of prodrug does not mean a poor therapeutic effect following oral administration because parent drug concentration may be low but it’s okay because pharmacologic effect comes from metabolite

okay since activity comes from metabolites so it is okay drug to be high Eh!

33
Q

Graph of parallel drug and metabolite lines:

True/false: This likely represents a kinetic profile of prodrugs

A

false

34
Q

Graph of parallel drug and metabolite lines:

True/false: It demonstrates metabolite formation rate limited kinetics

A

true

35
Q

Graph of parallel drug and metabolite lines:

True/false: The true half life of metabolite would be much shorter than the half life estimated from the graph

A

true

36
Q

Graph of parallel drug and metabolite lines:

True/false: This occurs when elimination rate of metabolite is faster than its formation rate

A

true

37
Q

Graph of parallel drug and metabolite lines:

True/false: Drugs of high Eh are associated with low F. A prodrug that has high Eh would exhibit minimal to no pharmacological activity after oral dosing

A

false

Pharmacokinetics (14 decks)

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