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Pharmacokinetics > Hepatic Drug Elimination Part 2 > Flashcards

Hepatic Drug Elimination Part 2 Flashcards

1
Q

What is clearance?

A

Can be applied to any organ and is the ability of the organ to extract and eliminate the drug that is presented to it by the blood

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2
Q

What is hepatic clearance?

A

Defined as the volume of blood that perfuses the liver and get cleared of the drug per unit of time

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3
Q

What is hepatic clearance used for?

A

Helpful to consider the concept of extraction ratio (ER).

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4
Q

How do you calculate CLh?

A
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5
Q

What is the average hepatic blood flow (Q)?

A

1.3-1.5L/min

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6
Q

What is ER?

A
  1. dimensionless quantity that compares the rate of drug elimination with the rate at which drug enters the liver
  2. The fraction of drug presented and eliminated by the liver during a single pass
  3. an index of how efficiently the liver clears the blood flowing through it off of a drug
  4. It is the fraction of the drug that is extracted by the liver during one passage
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7
Q

What are the categories of ER?

A

High ER (>0.7), intermediate ER (0.3 – 0.7), low ER (≤ 0.3)

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8
Q

What is the major factor of bioavailability decrease?

A

Pre-systemic elimination or first pass effect

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9
Q

What is first-pass effect?

A

Rapid metabolism of an orally administered drug before reaching the general circulation

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10
Q

What is biovailability in regards to ER?

A

A fraction of a dose of drug reaching to systemic circulation

F = 1-ER

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11
Q

What is the importance of calculating liver ER?

A

Provides a direct measurement of drug removal from the liver after oral drug administration

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12
Q

What parameters is ER dependent on?

A
  1. Blood flow to the liver (Q)
  2. The intrinsic ability of the liver to eliminate unbound drug (CLint)
  3. The fraction of the drug unbound in the blood (fup)
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13
Q

How do you calculate ER using parameters?

A
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14
Q

How do you calculate CLh using parameters?

A
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15
Q

What is the relationship between CLnr and CLh?

A

generally equal

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16
Q

How can you calculate CLr?

A

From the fraction of intact (unchanged) drug recovered in the urine

17
Q

What does it mean when a drug has a low ER?

A
  1. Also has a low intrinsic clearance, thus liver enzymes possess a smaller capacity to metabolize the drug
  2. The denominator part of the equation (QH + fup * CLint ), because CLint is smaller, QH (hepatic blood flow) will have a much greater influence than (fup * CLint).
  3. Qh + fup *Clint can be assumed to be equal to Qh
18
Q

How do you simplify the Clh based on low ER?

A
19
Q

What factors are effected by low ER drugs?

A
  1. CLh depends on free unbound fraction in plasma (fup) and intrinsic clearance
  2. Any change in the blood flow to the liver (Qh) such as congestive heart failure will not affect the clearance of low ER drugs
20
Q

What does it mean when a drug has a low ER?

A
  1. Such drug is said to have a high intrinsic clearance (CLint), thus the liver enzymes possess a greater capacity to metabolize the drug.
  2. Under this circumstance, in the denominator part of the above equation (QH + fup * CLint ), because CLint is greater, QH (hepatic blood flow) will have a very less influence than the ( fup * CLint ).
  3. Thus, (QH + fup * CLint ) can be ASSUMED to be equal to ( fup * CLint).
21
Q

How do you simplify the Clh based on high ER?

A
22
Q

What are the outcome of drug displacement?

A
  1. displacing bound drug molecules from plasma proteins will increase the fraction of unbound drug in the plasma (↑ fu);
  2. more unbound drug molecules will be able to leave the vascular system and enter into the liver where the
  3. unbound drug will be metabolized and hepatic drug clearance will increase
  4. , drug interactions that inhibit or induce the cytochrome P-450 enzyme system (↓ or ↑ CLint, respectively) will change the hepatic clearance of such drugs accordingly.
23
Q

What factors are effected by high ER drugs?

A
  1. hepatic clearance (CLH) depends solely on blood flow to the liver (QH)
  2. Any change in the free unbound fraction in plasma (fup) and intrinsic clearance (CLint) will not affect the hepatic clearance of high ER drugs.
  3. Hepatic clearance of drugs of high ER drugs does not change much when plasma protein binding displacement or enzyme induction or inhibition occurs due to drug interactions
24
Q

What is the rate limiting step for high ER drug metabolism?

A
  1. how much drug can be delivered to the liver because the capacity to metabolize drug is very large
  2. (CLH) is very sensitive to changes in liver blood flow (QH) due to congestive heart failure or liver disease

Pharmacokinetics (29 decks)

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