Drug Metabolism

Front 1

Name 4 consequences of drug metabolism.

Back 1

1. Elimination
2. Facilitation of Excretion
3. Alters drug activity
4. Produces toxic or carcinogenic metabolites

Front 2

Describe facilitation of excretion as a consequence of drug metabolism.

Back 2

Metabolism converts drug molecule to a less lipophilic, more water soluble compound. Thus, the new compound is less likely to be reabsorbed and more likely to be excreted.

Front 3

Describe alteration of drug activity as a consequence of drug metabolism.

Back 3

Most drugs interact with receptors to produce their effects so converting a drug to an inactive metabolite inhibits it from interacting with receptors. EXCEPTION: prodrugs are metabolized to biologically active cmpds

Front 4

Describe elimination as a consequence of drug metabolism.

Back 4

The original drug molecule is chemically modified and no longer present, thus, eliminated.

Front 5

Give 4 examples of "portals of entry". Why are they important?

Back 5

Liver, lung, skin, GI
They are impt because they are primarily responsible for metabolism

Front 6

Of the various portals of entry, why is the liver the most important?

Back 6

1. size
2. perfusion
3. location
4. cell type (hepatocytes have high concentration of enzymes)

Front 7

In simple terms, describe Phase I and Phase II reactions.

Back 7

A. Phase I = pre-synthetic; add nothing greater than MW=18 (water) to drug
B. Phase II = synthetic; add higher MW compounds

Front 8

Name 3 general examples of Phase I reactions.

Back 8

1. Oxidations
2. Reductions
3. Hydrolysis

Front 9

What is the most important Phase I reaction?

Back 9

Microsomal Mixed-Function Oxidase System

Front 10

Name the 2 components of the MMFOS. Which is more important and why?

Back 10

1. NADPH Cytochrome P450 Reductase
2. Cytochrome P450: the most impt b/c it is the site of drug substrate binding & oxygen activation

Front 11

In terms of enzyme properties, why is Cytochrome P450 unusual?

Back 11

has a very broad substrate specificity - thus the ability to metabolize many different compounds

Front 12

"Mixed Function Oxidase" means that molecular oxygen is split into 2 atoms. Where do these atoms end up?

Back 12

1 atom is on the drug metabolite and 1 atom forms water

Front 13

Since there are close to 60 human P450's and each P450 is a separate gene product, a classification scheme was devised. Use the scheme to define CYP3A4.

Back 13

CYP3A4
3 = family
A = subfamily
4 = individual enzyme

Front 14

What happens to the concentration of a CYP following chronic drug administration?

Back 14

CYP is induced & its concentration increases.

Front 15

5 things to keep in mind about CYP induction...

Back 15

1. induction requires a finite amt of time
2. induction process is reversed when inducing agent is withdrawn
3. induction can lead to enhanced rate of metabolism of the inducing agent itself and/or a 2nd drug
4. CYP induction is basis of some drug-drug intrxns
5. non-prescription drugs can also induce CYP

Front 16

Know how phenobarbital affects bishydroxycoumarin & how grapefruit juice affects felodipine.

Back 16

Administering phenobarbital decreases concetration of coumarin while grapefruit juice increases concentration of felodipine.

Front 17

Name 4 examples of Phase II reactions.

Back 17

1. Glucuronide synthesis by glucuronosyl transferase
2. Sulfate formation
3. Acetylation
4. Glutathione S-transferases

Front 18

Of the Phase II reactions, which is most important and why?

Back 18

Glucuronide syn by glucuronosyl transferase is most important b/c (1) induced by many of the same drugs that induce CYPs (2) end product - glucuronide - is much more hydrophilic compared to its precursor

Front 19

Where are sulfotransferases and glutathione S-transferases located? Are the enzymes inducible?

Back 19

Both are located in cytoplasm and glutathione S-transferases are induced by drugs & xenobiotics.

(note: glucuronosyl transferases are also inducible but they are microsomal enzymes - not cytosolic)

Front 20

Why are glutathione S-transferases important?

Back 20

Glutathione-S-transferase catalyzes the nucleophilic
conjugation of glutathione (GSH) with many diverse electrophilic
substrates. Glutathione conjugation is a major mechanism
of detoxification in mammals.

Front 21

Understand the importance of environmental factors on drug metabolism.

Back 21

In terms of adjusting a patient's dose, there is not a good test for determing how well a patient metabolized the drug due to environmental and genetic factors.

Front 22

Sulfotransferases produce sulfates. Are sulfates highly ionized or highly non-ionized at physiological pH? How does this affect their water solubility?

Back 22

Sulfates are highly ionized at physiological pH, leading to increased water solubility.

Front 23

The initial step in mercapturic acid synthesis is catalyzed by this family of Phase II enzymes.

Back 23

Glutathione S-transferases

Front 24

If a specific P450 is required to inactivate a drug but a person has very little amounts of the P450 due to variant alleles, how will this affect the drug response in the person? Will it be diminished or exaggerated?

Back 24

It will be exaggerated b/c the P450 is not inactivating it

Front 25

Are pharmacologically active molecules more lipophilic or lipophobic?

Back 25

lipophilic

thus, to facilitate excretion, drug metabolism converts the molecules into less lipophilic and more water-soluble compounds

Front 26

Describe metabolism of prodrugs.

Back 26

Prodrugs are metabolized to biologically active compounds

Front 27

Phase I hydrolysis reactions can occur in these 2 locations.

Back 27

plasma
liver

Front 28

Acutely, how does alcohol affect drug metabolism?

Back 28

acutely, alcohol can inhibit drug metabolism

Front 29

Does chronic alcohol consumption induce P450 system?

And what about excessive chronic consumption?

Back 29

Chronic consumption can induce P450 (specifically, can induce CYP2E1 which makes acetaminophen more hepatotoxic).

Excessive chronic alcohol intake, however, can cause decreased metabolism and eventually liver cirrhosis.

Front 30

These polymorphic Phase II enzymes produce acetylated cysteines.

Back 30

glutathione S-transferases

Front 31

Does P450 catalyze demethylation, methylation or conjugation?

Back 31

demethylation

Front 32

Where is P450 located within a cell?

Back 32

endoplasmic reticulum

Front 33

Which introduces active centers?

Phase I
Phase II

Back 33

Phase I

Front 34

Which of the Phase II reactions are inducible?

Back 34

Glucuronosyl transferase

Glutathione S-transferase

Front 35

Prodrugs are activated by this system.

Phase I or Phase II

Back 35

Phase I

Front 36

These reactions generally terminate drug action.

Phase I or Phase II

Back 36

Phase II

Front 37

TRUE OR FALSE

P450 converts NADP+ to NADPH.

Back 37

FALSE

NADPH supplies reducing equivalents for reduction of oxygen to water.

Front 38

Which enzyme does the following:

1) N-dealkylation
2) Aromatic hydroxylation
3) Aliphatic hydroxylation

Back 38

Cytochrome P450

Front 39

Name the 2 polymorphic Phase II enzymes

Back 39

N-acetyltransferase

Glutathione S-transferase