Drug Metabolism - Issar

Question 1

What are the Phase I (functionalization) reactions?

Answer 1

1. Oxidation
2. Reduction
3. Hydrolysis

Question 2

What are the Phase II (conjugation) reactions?

Answer 2

1. Glucuronide conjugation
2. Sulfate conjugation
3. N-acetylation conjugation
4. Methylation conjugation
5. Glutathione/amino acid conjugation

Question 3

What are the oxidation reactions?

Answer 3

• Addition of oxygen or removal of hydrogen
• Cytochrome P450 family

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

Question 4

What is aromatic hydroxylation?

Answer 4

Addition of OH functional group onto a benzene ring

***Ex: phenytoin

Question 5

What is aliphatic hydroxylation?

Answer 5

OH group added to aliphatic chain

***Ex: ibuprofen and secobarbital

Question 6

What is N-dealkylation?

Answer 6

Removes alkyl functional group

***Ex: Diazepam

Question 7

What are reduction reactions?

Answer 7

Addition of hydrogen or removal of oxygen atom

Ex: azo (-N=N-) or nitro groups (-NO2) form amines (-NH2)

Question 8

What are hydrolysis reactions?

Answer 8

Breakdown for an ester group

***Ex: aspirin to salicylic acid and cocaine to methyl ecgonine

Question 9

What are glucuronide conjugation reactions?

Answer 9

• Most common conjugation reaction!
• Uridine diphosphate-glucuronic acid (UDPGA) serves as a donor of glucuronic acid
• Enzymes = UDP-glucuronosyl transferases (UGTs)
• Natural substrates like bilirubin and thyroxine and morphine
• All glucuronide conjugation are catalyzed by microsomal enzymes

Question 10

What are sulfate conjugation reactions?

Answer 10

• 2nd MOST important conjugation reaction
• Enzyme system – saturable
• Sulfotransferases (SULTs) in the cytosol of liver
• Sulfate donor for reaction is an activated form of the sulfate known as 3’-phosphoadenosine-5’-phosphosulfate (PAPS)
• At least 11 sulfotransferase isoenzymes involved

Question 11

What are N-acetylation conjugation reactions?

Answer 11

• Catalyzed by N-acetyltransferases (cytosolic)
• Donor is acetyl-CoA
• Genetics plays important role in acetylation reactions.
• Rapid and slow acetylators; example Isoniazid

Question 12

What are methylation conjugation reactions?

Answer 12

• S-adenosylmethionine serves as the methyl donor.
• Methyltransferase enzymes catalyzes reaction.
• Ex: catechol O-methyltransferase (COMT) catalyzes transfer of a methyl group to a phenolic OH- of catecholamines.
• Ex: Phenylethanolamine N-methyl transferase (PNMT) methylates NE to epinephrine

Question 13

What are glutathione conjugation reactions?

Answer 13

• Glutathione-s-transferases (GSTs) catalyze the transfer of glutathione to reactive electrophiles.
• Physiological relevance – detoxification of free radicals, metals and electrophiles.
***Ex: Acetaminophen biotransformation
• Over 20 GST in humans; two subfamilies (cytosolic and microsomal)

Question 14

What is the role of pharmacogenomics in drug metabolism and drug response?

Answer 14

• Genetics can play a role in the type of metabolizer a person is and therefore how they will respond to certain drugs
• Slow v/s fast acetylators on isoniazid metabolism
• Ex: Biotransformation of codeine to morphine (CYP2D6)
***Ex: Warfarin metabolized by CYP2C9 – VKORC1 haplotype pt. can be more or less sensitive to warfarin

Question 15

What is enzyme induction?

Answer 15

o An increase in enzyme levels (CYP450) caused by a drug or environmental compounds (e.g. hydrocarbons)
o Increases metabolism of a drug
o If drug metabolism is increased pt will feel decreased drug effect
• Clinically now need to INCREASE DOSE

Question 16

What is enzyme inhibition?

Answer 16

o The P450 enzyme can be inhibited by
• A second drug acting as a competitive inhibitor (C) or
• An irreversible inhibitor (I)
o If drug metabolism is decreased pt will feel increased drug effect
• Clinically now need to DECREASE DOSE

Question 17

What are some examples of enzyme induction?

Answer 17

• Phenobarbital induces metabolism of itself or other drugs like warfarin and phenytoin
• Carbamazepine auto-induces
• Cigarette smoke increases levels of CYP1A2 → lowering theophylline interaction → increase theophylline levels
o Must increase theophylline dose in order for it to be effective

Question 18

What are some examples of enzyme inhibition?

Answer 18

• Fluoxetine (SSRI) inhibits CYP2D6 → ↑↑ imipramine
• Grape fruit juice → ↑↑ saquinavir by inhibiting CYP3A4
• Quinidine and ketoconazole inhibit P-gp and MDRP1 → ↑↑ digoxin

Question 19

What is hepatic clearance?

Answer 19

= blood flow rate x extraction ratio
o The volume of blood perfusing the liver that is cleared of the drug per unit of time
o Dependent on liver blood flow and extraction ratio

Question 20

What is hepatic blood flow?

Answer 20

Is a physiological Parameter that can be altered in diseased states

Question 21

What is the extraction ratio?

Answer 21

Is the measure of liver’s efficiency to eliminate the drug on a single pass

Question 22

What is free intrinsic clearance?

Answer 22

Is the maximal ability of the organ to eliminate the drug in absence of any flow imitations or binding to proteins

Question 23

What does it mean if there is a high extraction ratio?

Answer 23

o Drug is rapidly and extensively cleared
o Hepatic clearance depends upon hepatic blood flow
o If blood flow to liver increases then clearance rate increases
o Ex: propranolol decreases hepatic blood flow by reducing cardiac output; this drug deduces its own clearance when given orally

Question 24

What does it mean if there is a low extraction?

Answer 24

o Drug is not efficiently cleared
o Hepatic clearance dependent on protein binding and intrinsic clearance
o Increase in free clearance will increase hepatic clearance
o Examples
***Warfarin and phenytoin
• Smoking can increase intrinsic clearance for metabolism