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Foundations I > Hepatic Clearance & Bioavailability > Flashcards

Hepatic Clearance & Bioavailability Flashcards

1
Q

Clearance describes

A

the irreversible elimination of drug from the systemic circulation.

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2
Q

First pass elimination occurs during

A

the absorption phase before the drug reaches the systemic circulation

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3
Q

Hepatic Extraction Ratio (ERh)

A

Describes Efficiency of Metabolism (Extraction)

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4
Q

ERh assumes that

A

the liver is a well-stirred compartment and considers the passage of drug on a single pass through the liver

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5
Q

Qh

A

hepatic blood floow which is 1,500 ml/min

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6
Q

Ca

A

concentration of the drug that enters the liver (arterial side)

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7
Q

Rate of entry

A

Qh * Ca

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8
Q

Rate of exit

A

Qh * Cv

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9
Q

Cv

A

concentration of the drug exiting the liver (venous side)

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10
Q

Fraction escaping extraction

A

1 - ERh

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11
Q

Rate of elimination

A

Rate in - Rate out

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12
Q

Derivation of Extraction Ratio

A

rate of elimination / rate of presentation which is Qh * Ca

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13
Q

Extraction Ratio (ERh)

A

Ca - Cv / Ca

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14
Q

Drugs that have an extraction of greater than 0.7 are known to be

A

high extraction ratio drugs

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15
Q

ERh can be between

A

0 and 1

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16
Q

CL(H) =

A

QH x ER

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17
Q

Low ER =

A

0 to 0.3 equivalent to 0 and 750 ml/min hepatic blood

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18
Q

High ER

A

0.7 to 1.0 equivalent to 1050 ml/min hepatic blood flow

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19
Q

Everything in between 0.3 and 0.7 is

A

an intermediate ER drug, with hepatic blood flow of 750 ml/min

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20
Q

Qh

A

Renal blood flow which is 1,200 ml/min

21
Q

ER =

A

CL(H) / QH

22
Q

Amount of drug metabolized is dependent on:

A
  1. delivery of drug to the liver (Qh)
  2. fraction of drug unbound in the plasma (only unbound drug has access to DME)
  3. activity of the drug metabolizing enzymes for a particular drug (maximal rate of metabolism in vitro fu * Clint&raquo_space; Qh)
23
Q

Intrinsic Clearance

A

the inherent ability of the liver enzymes to metabolize a drug

24
Q

Cl int follows single substrate M-M kinetics

A
  • Vmax is the max rate of metabolism
  • Km is the affinity of the enzyme for the substrate (drug). Higher the affinity, lower the Km
25
Q

If fuC «< Km then

A

Cl int = Vmax / Km

26
Q

When low ERh

A

fuCl int &laquo_space;Qh
Clh = fu Cl int
Fh = 1

27
Q

High ERh is high

A

fu Cl int&raquo_space; Qh
ClH = Qh
Fh = 0

28
Q

The hepatic clearance of what type of drug will be MOST sensitive to changes in hepatic blood flow?
A. Low ERH
B. Intermediate ERH
C. High ERH

A

High ERH because Clh = Qh

29
Q

The hepatic clearance of what type of drug will be MOST sensitive to changes in intrinsic clearance?
A. Low ERH
B. Intermediate ERH
C. High ERH

A

Low ERH because Clh=fu * Cl int

30
Q

Hepatic clearance is the irreversible elimination of drugs from the systemic circulation by

A

metabolism in the liver

31
Q

ERH describes

A

the efficiency of hepatic metabolism of drugs on a single pass through the liver

32
Q

CLH is dependent on

A

hepatic blood flow, fraction unbound, and intrinsic clearance

33
Q

Hepatic clearance of low ERH drugs is dependent on

A

fraction unbound and intrinsic clearance while that of high ERH drugs is blood flow limited.

34
Q

What is the difference between the first pass and systemic hepatic metabolism?

A

First-Pass Metabolism:
- Occurs when a drug is administered orally or through routes passing through the liver before entering the systemic circulation.
- Results in a higher initial drug concentration, as the liver metabolizes a portion of the drug before it enters the bloodstream.

Systemic Hepatic Metabolism:
- Occurs after a drug has entered the systemic circulation, involving the metabolism of drug molecules that have already been distributed to various organs and tissues.
- Typically results in a lower drug concentration compared to the initial first-pass concentration, as the liver further modifies drug molecules for elimination or continued circulation.

35
Q

Which of the following can limit bioavailability?
A. Intestinal transport by P-gp and BCRP
B. Renal transport by P-gp and BCRP
C. Permeability of the drug
D. Gut CYP3A4 metabolism
E. High V
F. Liver metabolism by Phase I enzymes

A
  • A.
  • C. because it affects absorption
  • D.
  • F.
36
Q

Which of the following transporters limit drug
bioavailability?
A. OAT1
B. P-gp
C. MATE-2K
D. OATP1B1
E. BCRP

37
Q

Drugs are eliminated by liver metabolism during first pass and after distribution into

A

the systemic circulation.

38
Q

High ERH drugs have limited

A

hepatic bioavailability

39
Q

low ERH drugs have almost complete

A

hepatic bioavailability

40
Q

FH is dependent on

A
  • hepatic blood flow
  • fraction unbound
  • intrinsic clearance
41
Q

CHF and Cirrhosis contribute in a

A

decreased hepatic blood flow

42
Q

Causes of CLint changes:

A
  • Induction
  • Inhibition
  • Genetic polymorphisms
  • Disease
43
Q

Induction

A

when you take a drug that is stimulating or inducing enzymes, you’re going to have increased activity of these enzymes proteins

44
Q

Inhibition

A

we inhibit any other drug that is competing for the same binding site of the enzyme, you’re going to have less of that drug being metabolized because you have a second drug inhibiting it

45
Q

genetic polymorphisms

A

where the metabolizing enzyme, the protein itself is altered. So part of its sequence is changed so it changes its activity

46
Q

Disease

A

can also cause changes of Cl int like in the case of cerrosis where you loose a lot of liver functions and enzyme activity

47
Q

AUC oral is

A

independent of Qh and is the same for all ERh

48
Q

CLH and FH are dependent on

A

hepatic blood flow, fraction unbound, and intrinsic clearance.

49
Q

Specific changes in CLH and FH will be dependent on the

A

ERH of the drug

Foundations I (14 decks)

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