Exam 2 Metabolite Kinetics

Question 1

How are metabolites excreted?

Answer 1

biliary excretion

Question 2

How do metabolites contribute to drug response?

Answer 2

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

Question 3

What are two compounds and their metabolites?

Answer 3

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

Question 4

What are prodrugs?

Answer 4

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

Question 5

What is an example of a prodrug?

Answer 5

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)

Question 6

What is the rate limiting step?

Answer 6

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

Question 7

What is the equation for rate limiting step?

Answer 7

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

Question 8

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

Answer 8

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

Question 9

What is the true rate compared to the apparent rate?

Answer 9

true rate → the true capacity of the person eating apples

apparent rate → what you end up seeing

Question 10

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

Answer 10

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

Question 11

What is the apparent rate?

Answer 11

the metabolite formation rate

Question 12

What is the true rate?

Answer 12

the metabolite elimination rate

Question 13

What happens when apparent rate is slower than true rate?

Answer 13

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

Question 14

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

Answer 14

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)

Question 15

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

Answer 15

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

Question 16

How is metabolite elimination rate accurately estimated?

Answer 16

metabolites should be administered

Question 17

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

Answer 17

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

Question 18

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

Answer 18

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

Question 19

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

Answer 19

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

Question 20

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

Answer 20

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

Question 21

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

Answer 21

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

Question 22

What is the typical pattern for most drugs?

Answer 22

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

Question 23

What is the typical pattern for most prodrugs?

Answer 23

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

Question 24

What is an example of formation limited?

Answer 24

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

Question 25

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?

Answer 25

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

Question 26

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

Answer 26

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

Question 27

What is an example of elimination-limited?

Answer 27

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

Question 28

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

Answer 28

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)

Question 29

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

Answer 29

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)

Question 30

What is the first pass effect with active metabolites?

Answer 30

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

Question 31

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

Answer 31

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)

Question 32

What happens when prodrugs of high Eh are administered?

Answer 32

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!

Question 33

Graph of parallel drug and metabolite lines: True/false: This likely represents a kinetic profile of prodrugs

Answer 33

false

Question 34

Graph of parallel drug and metabolite lines: True/false: It demonstrates metabolite formation rate limited kinetics

Answer 34

true

Question 35

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

Answer 35

true

Question 36

Graph of parallel drug and metabolite lines: True/false: This occurs when elimination rate of metabolite is faster than its formation rate

Answer 36

true

Question 37

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

Answer 37

false