Drug Metabolism

Question 1

Most of the Phase 1 reactions are part of

Answer 1

cytochrome p450 system

Question 2

most of the phase 1 reactions are..

Answer 2

oxidations (OH, SH, NH2, COH, COOH) in addition there are hydrolysis reactions, reduction, dehalogentation, dehydrogenation, and dealkylation

Question 3

phase 1 reactions’ role

Answer 3

to prepare lipophilic drugs for the addition of functional groups or add them
it doesnt necessarily convert inactive to active; it can make something an active metabolite, inactive metabolite, or convert pro-drug into drug

Question 4

most of the phase 2 reactions are..

Answer 4

carried out by transferases

Question 5

phase 2 tends to be _____, while phase 1 is _______

Answer 5

conjugation; oxidation

Question 6

most common conjugation =

Answer 6

glucuronidation

Question 7

glucuronidation is often followed by:

Answer 7

sulfation

Question 8

other conjugations carried out in phase 2:

Answer 8

of amino acids; acetylation and methylation

Question 9

all of phase 2 focuses on using the reactions to do what

Answer 9

get the drug out of the body

Question 10

2 main goals of phase 2

Answer 10

enhance solubility and to detoxify (to reduce the toxic effects of the parent or metabolized drug and usually it creates non-toxic metabolites

Question 11

the Cytochrome P450 isoenzyme is

Answer 11

responsible for 75% of drug metabolism and is predominately responsible for phase 1 of drug metabolism

Question 12

cytochrome P450 transfers e-

Answer 12

between oxidized (fe3+) and reduced (fe2+) forms of iron

Question 13

how many CYP genes in nature vs. in humans

Answer 13

6,000 vs. 57

Question 14

Classification system CYP2D6

Answer 14

2 = family d = subfamily 6 = isoenzyme

Question 15

Humans have ____ CYP families and ______ CYP enzymes in drug metabolism

Answer 15

4 families and 15 enzymes

Question 16

90% of drug metabolism is carried out by:

Answer 16

1A2, 2C9, 2C19, 2D6, 2E1 (alcohol) , and 3A4 (HIV drug that we learned about)

Question 17

location of cyp450

Answer 17

smooth ER of liver and kidney and in enterocytes (contributing to first pass metabolism)

Question 18

cyp450 activity

Answer 18

substrates- drugs, chemicals or hormones that undergo biotransformation by cyp450 (acetaminophen)
inducers- that enhance the enzyme activity and increase metabolism of substrate (ciproflaxin)
inhibitors- decrease metabolism of substrate (phenytoin)

Question 19

substrate activity depends on

Answer 19

km, the concentration of substrate required to reach 50% vmax

Question 20

small km

Answer 20

means you only need a small amount of substrate to be very active

Question 21

large km

Answer 21

means you need alot of substrate to reach vmax

Question 22

example of the substrate activity dependence on km

Answer 22

at low ethanol conc. the enzyme with the low km (ADH) predominates metabolism. at high ethanol concentrations CYP2E1 takes over, which has a high km

When you hear about people that can metabolize alcohol faster than others, its because of conformational changes. So if you constantly expose your body to alcohol, you actually metabolize it better than those who don’t drink it on a regular basis

Question 23

Substrate selectivity

Answer 23

determined by molecular, physiologic, biochemical, and other factors
stereoisomers
acidic/basic
lipophilicity

Question 24

Example of substrate selectivity

Answer 24

S-warfarin and R-warfarin do not have the same CYP metabolism (S-warfain accounts for 70% of activity and is metabolized by 2C9) (R-warfain is metabolized by 3A4, 1A1 and 1A2)

Question 25

Can you predict substrate selectivity by class?

Answer 25

No- example = all of the statins on the slide have different CYP metabolism

Question 26

Most common cause of drug-drug interactions and 2 possible things that they can do

Answer 26

cyp inhibitors and they can increase the bioavailability of a drug or decrease the activity of a prodrug that needs to be activated

Question 27

Example of CYP inhibitor

Answer 27

Grapefruit which has furanocoumarins that inhibit cyp3A4 for 24-72 hours. This is a problem for simvistatin which is good for lowering cholesterol but can lead to muscle and liver damage and it is metabolized by cyp3a4 for if you inhibit that then you have more of the drug hanging around and you have more negative side effects

Question 28

inducers can either

Answer 28

increase the effect of a drug by increasing conversion form prodrug OR
decrease effect of the drug by increasing elimination

Question 29

the inducible cyp’s

Answer 29

2A, 2B, 2C, 2E, and 3A

Question 30

inducers cause a _____mediated_________

Answer 30

nucelar-receptor mediated increase in gene transcription of the cyp enzymes

Question 31

genetic polymorphism

Answer 31

genetic change that exists in at least 1% of the population and for cyp there are polymorphisms that affect the enzyme activity

Question 32

extensive

Answer 32

normal amount of enzyme and drug response (2 genes that work)

Question 33

intermediate

Answer 33

at least 1 gene isnt working properly and you may have less response or more side effects from certain drugs

Question 34

poor

Answer 34

variants in both genes; much less enzyme than normal; at high risk for drug side effects; may need higher dose of a drug in rare case where it needs to be broken down before it works

Question 35

ultra rapid

Answer 35

extra copies of these genes and much more enzyme than normal; may break down drugs so quickly that it wont work at usual doses; they may need a lower dose of the drug in the case where it needs to be broken down in order to work

Question 36

how does the metabolizer profile have an effect clinically

Answer 36

take the example of codeine- people come in saying that its not doing anything and they are labelled as drug-seekers, when really, it may not be doing anything because 7% of whites, 3% of blacks, and 1% of asians are poor metabolizers and have polymorphisms in 2D6
and for ultra rapid metabolizers it may be getting worse due to elevated concentrations of morphine

Question 37

how can you tell if your patient has activity of 2d6 or 2c19

Answer 37

array testing with cheek swab

Question 38

what can p-glycoproteins do

Answer 38

they can move drugs out or into the cell against concentration gradients; they actively extrude drugs back into intestinal lumen; are also present in ovaries, testes, kidneys, placenta, liver bile duct and blood-brain barrier

Question 39

what are p-glycoproteins

Answer 39

ATP-binding cassette transporters (ABC transporters)

Question 40

why are p-glycoproteins important for metabolism of drugs

Answer 40

there are many inducers and inhibitors of p-glycoproteins

Question 41

drug interactions

Answer 41

account for significant amount of ADR; CYP enzymes account for majority of significant drug-drug interactions

Question 42

what can you do to prevent drug-drug interactions?

Answer 42

recognize high risk patients (elderly and those with renal and/or liver dysfunction) and high risk meds

Question 43

high risk meds for drug-drug interactions

Answer 43

polypharmacy (5+ drugs), digoxin, warfarin and anticoagulants, sedatives, pain relievers, antibiotics

Question 44

acetaminophen is…

Answer 44

the leading cause of fulminant hepatic failure in the US and worldwide

Question 45

at therapeutic dosing, acetaminophen is

Answer 45

sulfated and then detoxified/eliminated

Question 46

at overdosing, acetaminophen is

Answer 46

oxidized by cyp450 (specifically CYP2E1) and made into NAPQI. NAPQI binds to proteins in your liver and causes severe liver toxicity