Hepatic Drug Elimination

Question 1

What are the 2 methods how drugs can be eliminated?

Answer 1

Renal and hepatic clearance assumed they are independent and additive

Question 2

Describe drugs that are eliminated highly by hepatic metabolism?

Answer 2

Are dependent on the intrinsic ability of metab0lizing enzymes displaying large inter-individual variability due to generic and environmental factors

Question 3

Describe drugs that are eliminated primarily by renal excretion unchanged?

Answer 3

Are highly dependent on the glomerular filtration rate (GFR) and blood flow to the kidney -> which display less inter-individual variability

GFR is relatively constant among individuals with normal renal function

Question 4

What is clinically useful information for determining drug elimination?

Answer 4

The percentage of drug excreted as unchanged and the percent of drug metabolized

Question 5

What happens if the renal excretion pathway becomes impaired?

Answer 5

Less drug will be excreted because lipophilic drugs can not be metabolized for excretion therefore drug will accumulate in the body. Increasing toxicity

Question 6

How do you calculate k for excretion

Answer 6

Question 7

What is ke?

Answer 7

Elimination rate constant due to excretion

For drugs that is easily obtained wither from drug literature in the form of fraction of dose excreted unchanged or urine data

Question 8

How do you calculate fraction of dose excreted in urine?

Answer 8

Question 9

What happens if hepatic excretion pathway is impaired?

Answer 9

More drug will be excreted unchanged

Question 10

What is km?

Answer 10

Elimination rate constant due to metabolism

Km = kmA + Kmart + kmC + etc

Question 11

What are the approaches to obtain km?

Answer 11

1. Drug literature in the form of fraction of drug dose metabolized
2. The difference between k and ke

Question 12

How do you calculate km by fraction of drug metabolized?

Answer 12

Question 13

Describe the relationship between fm and fe?

Answer 13

fm can indirectly be obtained if fe (fraction of drug excreted unchanged)

fm = 1-fe

Question 14

How can km be determined by k and ke?

Answer 14

Question 15

What is extrahepatic metabolism and name an example of a drug that undergoes it?

Answer 15

Nitroglycerin is metabolized extensively outside the live

Question 16

How do you assess extrahepatic metabolism?

Answer 16

Calculate hepatic (metabolic) and renal clearance of the drug and compare these clearances to total body clearance

Question 17

What order is the drug metabolism and excretion assumed to be?

Answer 17

First order

Question 18

What are most drugs 1st order metabolic and elimination kinetics?

Answer 18

1. Concentration of drug metabolizing enzymes in the body is constant
2. Therapeutic (target) drug concentrations in plasma are much lower and don’t saturate the enzymes that are involved in the metabolism for most drugs
3. Most drugs are presented to metabolizing enzymes as concentrations well below the enzymes maximal capacity
4. Availability of enzymes is not an issu
5. Rate of drug metabolism will only depend on the concentration of the drug
6. Drug elimination by metabolism for most drugs is 1st order

Question 19

Describe the enzyme kinetics if there is a higher drug concentration?

Answer 19

Metabolizing enzymes have limited capacity, they saturate resulting in drug elimination by metabolism occurs at a constant maximal rate (zero order_

Question 20

What is non-linear Michaelis -Menten kinetic equation?

Answer 20

Describe the rate of drug elimination by metabolism depends on both drug concentration and the concentration of drug metabolizing enzymes

The hyperbolic (nonlinear) relationship between enzymatic reaction velocity and drug concentration

Question 21

What does enzyme kinetics consider?

Answer 21

1 mole of drug interacts with 1 mole of an enzyme to form enzyme-drug intermediate which further decomposes to product (metabolite)

Question 22

What does MM equation assume?

Answer 22

The rate of an enzyme reaction is dependent on the concentrations of both the enzyme and the drug

Question 23

Describe the kinetics when drug concentration is low compared to the enzyme concentration?

Answer 23

There is an abundance of enzymes to catalyze the reaction the rate of metabolism is 1st order

Question 24

Describe the kinetics when drug concentration is plasma is higher than enzyme concentration?

Answer 24

All enzymes become occupied with drug, the rate of metabolism is maximum, the rate process becomes 0 order

Question 25

What is V?

Answer 25

Velocity (rate) of the forward metabolic reaction

Question 26

What is Vmax?

Answer 26

The max rate of metabolism

Question 27

What is Km?

Answer 27

Michaelis constant

The concentration of the drug at which the rate of metabolism occurs at half the maximum rate (Vmax/2 or 0.5Vmax)

Question 28

What does it mean to have a high Km value?

Answer 28

Higher concentration will be necessary to saturate drug metabolizing enzyme

Question 29

How do you calculate km by MM kinetics?

Answer 29

Question 30

Describe how MM is used to obtain a linear relationship?

Answer 30

Question 31

Describe the components of a Line Weaver Burke plot?

Answer 31

A: b= intercept
B: m = slope
C: Km/Vmax
D: -1/Km
E: 1/Vmax

Question 32

How is intrinsic clearance relate to Line weaver Burke?

Answer 32

Inverse of slope (Vmax/Km)

Question 33

What is CLint?

Answer 33

A pure measure of the inherent ability of the liver enzymes to metabolize unbound drug in the blood (fu,p)

Distinct characteristic of a particular drug

CLint = Vmax/Km

Used to predict CLh

Question 34

What occurs if there was a change in of an enzyme ?

Answer 34

Change in CLh of a drug that is significantly metabolized by a particular enzyme

Question 35

How is CLint predicted?

Answer 35

Based on in vitro data from MM analysis

Question 36

What is hepatic clearance?

Answer 36

A concept that characterizes drug elimination based on the rate of blood flow (Q), the intrinsic clearance of the liver (CLint) and unbound fraction of a drug in the plasma (fup)