Hepatic Drug Metabolism

Question 1

Which acronym can be used to remember the 4 phases of pharmacokinetics?

Answer 1

A - Absorption
D - Distribution
M - Metabolism
E - Excretion

Question 2

What is drug metabolism?

Answer 2

The chemical alteration of a drug by the body.

Question 3

What blood vessel will drugs first enter once they are absorbed via the GI tract?

Answer 3

The portal vein.

Question 4

What is meant by first-pass metabolism?

Answer 4

A process in which a drug administered by mouth is absorbed from the gastrointestinal tract and transported via the portal vein to the liver, where it is metabolized. As a result, in some cases only a small proportion of the active drug reaches the systemic circulation and its intended target tissue.

Question 5

In what ways are drugs eliminated from the body?

Answer 5

Mostly in urine by the kidneys, and sometimes in bile.

Question 6

What is involved in Phase I drug metabolism?

Answer 6

It consists of reduction, oxidation, or hydrolysis reactions. These reactions serve to convert lipophilic drugs into more polar molecules by adding or exposing a polar functional group such as -NH2 or -OH.

Question 7

What group of drugs can be made more pharmacologically active by Phase I metabolism?

Answer 7

Prodrugs.

Question 8

What is involved in Phase II drug metabolism?

Answer 8

Phase II reactions consist of adding hydrophilic groups to the original molecule, a toxic intermediate or a nontoxic metabolite formed in phase I, that requires further transformation to increase its polarity. These reactions include conjugation reactions, glucuronidation, acetylation, and sulfation.

Question 9

How could a drug go straight to Phase II metabolism and therefore bypass Phase I metabolism?

Answer 9

If the drug already has a suitable functional group as part of its chemical structure.

Question 10

For many drugs, what does Phase I do to the pharmacological activity of the drug?

Answer 10

Decreases its pharmacological activity - if its a pro-drug it increases pharmacological activity.

Question 11

What are the 2 main reasons for adding a functional group during Phase I metabolism?

Answer 11

1. To increase the polarity of the drug

2. To provide a site for Phase II reactions

Question 12

Which reactions are most common in Phase I metabolism?

Answer 12

Oxidation
Reduction
Hydrolysis

Question 13

What is the name of the superfamily of enzymes which aid in oxidative Phase I metabolism reactions?

Answer 13

Cytochrome P450 enzymes.

Question 14

What are Cytochrome P450 enzymes?

Answer 14

A superfamily of enzymes containing haem as a cofactor that functions as monooxygenases. These proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown.

Question 15

Where are Cytochrome P450 enzymes located within cells?

Answer 15

On the smooth endoplasmic reticulum.

Question 16

What 3 things do Cytochrome P450 enzymes require the presence of in order to function?

Answer 16

1. Molecular oxygen
2. NADPH
3. NADPH cytochrome P450 reductase

Question 17

Cytochrome P450 enzymes need molecular oxygen, NADPH, and NADPH cytochrome P450 reductase to function - what are these factors collectively referred to as?

Answer 17

Mixed function oxidase system.

Question 18

What are the 4 major Cytochrome P450 enzyme Isoforms and approximately what percentage of current drugs do they metabolise?

Answer 18

• CYP3A (50% drugs)
• CYP2D6 (25% drugs)
• CYP2C9 (15% drugs)
• CYP1A2 (5% drugs)

Question 19

In the names of the Cytochrome P450 isoforms, e.g. CYP2D6, what does each letter/number denote?

Answer 19

• The first number denotes the isoform family.
• The letter denotes the genetic subfamily.
• The second number denotes the individual gene product.

Question 20

The process of drug oxidation involved what 2 steps?

Answer 20

Oxidation and reduction.

Question 21

The oxidation of a drug by Cytochrome P450 involves both oxidation and reduction steps. Describe these.

Answer 21

Cytochrome P450 catalyzes the transfer of one oxygen atom to the substrate (drug) while the other oxygen atom is reduced to water.
E.g. DH + O2 + NADPH + H+ goes to DOH + H2O + NADP+.

Question 22

Name 2 oxidation reactions in Phase I that DO NOT involve the CYP450 system.

Answer 22

1. Ethanol is metabolised by alcohol dehydrogenase.

2. Many biologically active amines such as noradrenaline and 5-HT are inactivated by monoamine oxidase.

Question 23

What Phase I reaction does aspirin undergo and what is the product?

Answer 23

Aspirin (acetylsalicylic acid) is hydrolyzed to salicylic acid.

Question 24

Where in the cells of the liver are the conjugative enzymes involved in Phase II metabolism located?

Answer 24

Some (glucuronyl transferases) are located on the Endoplasmic Reticulum, next to the CYP450s, and some are located in the cytosol.

Question 25

Why might some end products of liver metabolism be excreted in the faeces rather than urine?

Answer 25

If they are larger molecules.

Question 26

Once a drug is entering Phase III transport, where are the 2 options it can travel to in order to leave the liver?

Answer 26

Into the sinusoids to travel into the central vein to enter systemic circulation for elimination via the kidneys, or into the canaliculi to enter the bile for elimination via the faeces.

Question 27

Will drugs conjugated with glucuronide will most likely be eliminated through urine or bile? Why?

Answer 27

Bile, because adding glucuronide significantly increases the molecular weight of the drug, and larger molecules are eliminated via bile.

Question 28

Should drug doses be given higher or lower in neonates? Give 2 reasons why.

Answer 28

Lower

1. Hepatic drug-metabolizing enzyme systems are immature.
2. Renal clearance is inefficient.

Question 29

What is a neonate?

Answer 29

An infant less than 4 weeks old.

Question 30

How does metabolic clearance of drugs in children compare to that in adults? Why is this?

Answer 30

Metabolic clearance can be quicker in children than in adults because CYPs are mature and the relative liver mass and hepatic blood flow are higher.

Question 31

What is considered in determining the prescribed dosages of drugs for children?

Answer 31

Age and body surface area.

Question 32

Describe how age affects drug metabolism - in other words, describe drug metabolism in older adults.

Answer 32

Overall capacity for hepatic drug metabolism, particularly phase I reactions, is reduced, because the relative liver mass and hepatic blood flow are lower.

Question 33

Drug interactions at the level of hepatic metabolism are commonly due to interaction at what?

Answer 33

CYP450 enzymes.

Question 34

In which 2 ways can CYP450 enzymes be affected and how does this change the metabolism of drugs?

Answer 34

1. CYP450 enzyme induction results in more rapid metabolism of drugs.
2. CYP450 enzyme inhibition results in reduced metabolism of drugs.

Question 35

How does long-term administration of drugs affect CYP450 enzyme activity?

Answer 35

Long-term administration of drugs often induces CYP450 enzyme activity by enhancing the rate of synthesis or reducing the rate of degradation of the CYP450 enzymes.

Question 36

Usually, long-term administration of drugs can induce CYP450 activity, leading to more rapid metabolism of the drug and therefore lower plasma levels. What drug type is an exception to this?

Answer 36

Pro-drugs, whose biological effects will increase.

Question 37

What affect does St. John’s Wort have on many P450 enzymes? What does this mean for drug metabolism? Give 3 examples of drugs whose metabolism would be affected.

Answer 37

It induces the activity of many P450 enzymes. This increases the metabolism, and therefore reduces the plasma concentration, and potentially the therapeutic efficacy, of certain drugs such as warfarin, anti-epileptics, oral contraceptives.

Question 38

Name a drug which is a CYP450 enzyme inhibitor. What drug class does this drug belong to?

Answer 38

Cimetidine - a histamine H2-receptor antagonist.

Question 39

Where can you look to check interactions between drugs?

Answer 39

British National Formulary.

Question 40

Describe what is meant by genetic polymorphisms of the CYP450 enzymes.

Answer 40

Mutations in a CYP gene can lead to functional alterations, such as increased or decreased activity. If a mutant allele occurs at a frequency of at least one percent in a population, it is referred to as a pharmacogenetic polymorphism.

Question 41

How will the efficacy of an active drug be affected by poor metaboliser?

Answer 41

Increased efficacy

Question 42

How will the efficacy of an active drug be affected by a rapid metaboliser?

Answer 42

Decreased efficacy.

Question 43

How will the efficacy of a pro-drug be affected by a poor metaboliser?

Answer 43

Decreased efficacy.

Question 44

How will the efficacy of a pro-drug be affected by a rapid metaboliser?

Answer 44

Increased efficacy.

Question 45

In what way does liver cirrhosis affect drug metabolism?

Answer 45

Impaired liver function means decreased drug-metabolising capacity. This results in increased bioavailability resulting from impaired first-pass metabolism.

Question 46

Define bioavailability.

Answer 46

The proportion of administered drug which reaches systemic circulation unchanged and is thus available for distribution to the site of action.

Question 47

Other than by increasing bioavailability of drugs, how else may liver disease/cirrhosis lead to toxic drug levels?

Answer 47

• Liver damage can cause hypoproteinaemia.
• This would result in decreased protein binding of drugs.
• This allows more unbound and pharmacologically active drug to circulate and readily bind to receptors.

Question 48

Name 3 types of conjugation reactions found in Phase II drug metabolism.

Answer 48

• Glucuronidation
• Acetylation
• Sulfation