Exam 1

Question 1

What is the purpose of biotransformation?

Answer 1

To promote drug elimination from the body

Question 2

How is a drug with a MW<350 excreted?

Answer 2

By the kidney

Question 3

How is a drug with a MW>350 excreted?

Answer 3

By the liver

Question 4

Codeine starts as a what and becomes what? (regarding biotransformation)

Answer 4

Codeine (prodrug) > Morphine (active metabolite**)

*Metabolized to become active

Question 5

Diazepam starts as what and becomes what? (regarding biotransformation)

Answer 5

Diazepam (active drug) > Nordiazepam (active metabolite) and Ozazepam (active metabolite)
*Metabolites are more active than parent drug

Question 6

Acetaminophen starts as what and becomes what? (regarding biotransformation)

Answer 6

Acetaminophen (active drug) > N-acetyl-p-benzo-quinone imine (toxic metabolite**)
*Metabolized to toxic metabolites

Question 7

Describe the process of acetaminophen becoming a toxic metabolite

Answer 7

1. Acetaminophen metabolized (can be induced by ethanol)
2. Conjugated with glutathione (GSH)
3. GSH supply gets saturated
4. Increased production of oxidative metabolites (oxidative stress) leads to hepatotoxicity
5. Some GSH conjugates are toxic

Question 8

How does ethanol induce acetaminophen metabolism?

Answer 8

Through CYP2E1

Question 9

What is the purpose of a phase I reaction?

Answer 9

Modification of molecule:
To convert lipid soluble, non-ionized compounds to more ionized, hydrophilic metabolites
(some metabolites are readily excreted after phase I, others must go to phase II)

Question 10

What is the purpose of a phase II reaction?

Answer 10

Conjugation:

Adds an ionized, charged particle to a phase I metabolite to form a more polar and hydrophilic conjugate

Question 11

What is the most common Phase I reaction?

Answer 11

Oxidation reaction

Question 12

Are phase I reactions specific or nonspecific to compounds?

Answer 12

Compound NON-specific (meaning no specific enzymes are metabolizing a particular drug)

Question 13

How do enzymes work in a phase I reaction?

Answer 13

• They are nonspecific to specific drugs

- Work by attacking specific FUNCTIONAL GROUPS which affects multiple drugs

Question 14

Which functional groups do enzymes “unmask” in a phase I reaction?

Answer 14

OH (major)
SH
NH2

Question 15

What is the major enzyme of Phase I Oxidation? Describe this enzyme

Answer 15

CYP450

• Family of enzymes found in the LIVER
• Are MICROSOMAL enzymes (meaning they are inducible/can be stimulated)

Question 16

What is the primary function of CYP450

Answer 16

• Oxidation (formation of OH) of multiple drugs and foreign molecules during Phase I rxns
• Acts as a “handle” for phase II rxns

Question 17

What are the 3 subtypes of P450?

Answer 17

3A4
2D6
2E1
*All have different affinities for different substrates

Question 18

What is the purpose of the 3A4 enzyme?

Answer 18

Metabolizes >50% of drugs

*3A4 part of P450 family

Question 19

What is the purpose of the 2D6 enzyme?

Answer 19

Polymorphism impairs codeine metabolism (codeine > morphine)

*2D6 part of P450 family

Question 20

What is the purpose of the 2E1 enzyme?

Answer 20

Metabolizes and is induced by alcohol
(Ethanol induces metabolism of acetaminophen AND itself)
*2E1 part of P450 family

Question 21

What is the only Phase II enzyme that is microsomal and inducible?

Answer 21

Glucuronyl transferase

Question 22

What are the inducers of the 1A2 enzyme?

Answer 22

Smoking, chargrilled foods

Question 23

What are the inducers of the 2A6, 2B6, 2C8, 2C9, 2C18, 3A4 enzymes?

Answer 23

Barbituates/phenobarbital, St John’s warts

Question 24

What is the inducer of 2E1?

Answer 24

Ethanol

Question 25

What is the inhibitor of 3A4? Is the similar to competitive or non-competitive antagonists?

Answer 25

``` Grapefruit juice Competitive antagonist (competes for same active site but not actually a substrate) ```

Question 26

What is the inhibitor of 2D6? Is the similar to competitive or non-competitive antagonists?

Answer 26

Fluoxetine (Prozac) | Non-competitive antagonist (forms tight complex at allosteric site causing reversible inhibition)

Question 27

Name the Phase I CYP450-independent (non-microsomal) oxidative rxns:

Answer 27

- Alcohol dehydrogenase | - Monoamine oxidase

Question 28

Name the Phase I CYP450-independent (non-microsomal) NON-oxidative rxns:

Answer 28

- Reductive rxns (add H+ to compound): warfarin inactivated by CYP2A6 - Hydrolytic rxns (Occur in plasma and in many tissues): esterases and amidases

Question 29

Where do the majority of conjugation (phase II) rxns occur? What are the mediated by?

Answer 29

- Occur in the liver | - Mediated by glucuronidation and UGTs

Question 30

What is the end product of Phase II rxns?

Answer 30

- Decreased lipid solubility - Polar and inactive - Have a larger molecular weight - Readily eliminated

Question 31

Which functional groups are most commonly conjugated with glucuronic acid?

Answer 31

OH, SH, NH2

Question 32

Provide an example in which the phase II rxn occurs before the phase I rxn. Describe the process.

Answer 32

Example: Isoniazid 1. Acetylation by NAC (phase II) 2. Hydrolysis (phase I)

Question 33

What does acetylation/hydrolysis of isoniazid result in

Answer 33

Toxic metabolites

Question 34

Name and describe the 2 examples of Phase I polymorphisms

Answer 34

1. CYD2D6: involves metabolism of codeine to morphine (decreased 2D6 = codeine won't work) 2. Alcohol flush rxn: deficiency in aldehyde dehydrogenase leads to accumulation of acetaldehyde (cannot tolerate alcohol)

Question 35

Name and describe the 2 examples of Phase II polymorphisms

Answer 35

1. Butyrylcholinesterase: succinylcholine, local anesthetics (high degree of polymorphisms) 2. Fast and slow acetylators: seen with isoniazid (give small dose to slow metabolizers)

Question 36

Describe the process of "freeing of drugs"

Answer 36

finish later

Question 37

Describe the half lives of drugs that enter enterohepatic circulation. Name an example.

Answer 37

Usually have long half lives | Ex: birth control