Hepatic Clearance & Bioavailability

Question 1

Clearance describes

Answer 1

the irreversible elimination of drug from the systemic circulation.

Question 2

First pass elimination occurs during

Answer 2

the absorption phase before the drug reaches the systemic circulation

Question 3

Hepatic Extraction Ratio (ERh)

Answer 3

Describes Efficiency of Metabolism (Extraction)

Question 4

ERh assumes that

Answer 4

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

Question 5

Qh

Answer 5

hepatic blood floow which is 1,500 ml/min

Question 6

Ca

Answer 6

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

Question 7

Rate of entry

Answer 7

Qh * Ca

Question 8

Rate of exit

Answer 8

Qh * Cv

Question 9

Cv

Answer 9

concentration of the drug exiting the liver (venous side)

Question 10

Fraction escaping extraction

Answer 10

1 - ERh

Question 11

Rate of elimination

Answer 11

Rate in - Rate out

Question 12

Derivation of Extraction Ratio

Answer 12

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

Question 13

Extraction Ratio (ERh)

Answer 13

Ca - Cv / Ca

Question 14

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

Answer 14

high extraction ratio drugs

Question 15

ERh can be between

Answer 15

0 and 1

Question 16

CL(H) =

Answer 16

QH x ER

Question 17

Low ER =

Answer 17

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

Question 18

High ER

Answer 18

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

Question 19

Everything in between 0.3 and 0.7 is

Answer 19

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

Question 20

Qh

Answer 20

Renal blood flow which is 1,200 ml/min

Question 21

ER =

Answer 21

CL(H) / QH

Question 22

Amount of drug metabolized is dependent on:

Answer 22

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)

Question 23

Intrinsic Clearance

Answer 23

the inherent ability of the liver enzymes to metabolize a drug

Question 24

Cl int follows single substrate M-M kinetics

Answer 24

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

Question 25

If fuC <<< Km then

Answer 25

Cl int = Vmax / Km

Question 26

When low ERh

Answer 26

fuCl int << Qh Clh = fu Cl int Fh = 1

Question 27

High ERh is high

Answer 27

fu Cl int >> Qh ClH = Qh Fh = 0

Question 28

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

Answer 28

High ERH because Clh = Qh

Question 29

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

Answer 29

Low ERH because Clh=fu * Cl int

Question 30

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

Answer 30

metabolism in the liver

Question 31

ERH describes

Answer 31

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

Question 32

CLH is dependent on

Answer 32

hepatic blood flow, fraction unbound, and intrinsic clearance

Question 33

Hepatic clearance of low ERH drugs is dependent on

Answer 33

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

Question 34

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

Answer 34

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.

Question 35

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

Answer 35

- A. - C. because it affects absorption - D. - F.

Question 36

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

Answer 36

- B. - D. - E.

Question 37

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

Answer 37

the systemic circulation.

Question 38

High ERH drugs have limited

Answer 38

hepatic bioavailability

Question 39

low ERH drugs have almost complete

Answer 39

hepatic bioavailability

Question 40

FH is dependent on

Answer 40

- hepatic blood flow - fraction unbound - intrinsic clearance

Question 41

CHF and Cirrhosis contribute in a

Answer 41

decreased hepatic blood flow

Question 42

Causes of CLint changes:

Answer 42

- Induction - Inhibition - Genetic polymorphisms - Disease

Question 43

Induction

Answer 43

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

Question 44

Inhibition

Answer 44

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

Question 45

genetic polymorphisms

Answer 45

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

Question 46

Disease

Answer 46

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

Question 47

AUC oral is

Answer 47

independent of Qh and is the same for all ERh

Question 48

CLH and FH are dependent on

Answer 48

hepatic blood flow, fraction unbound, and intrinsic clearance.

Question 49

Specific changes in CLH and FH will be dependent on the

Answer 49

ERH of the drug