Drug metabolism

Question 1

First pass effect dosing

Answer 1

Need higher concentration orally vs. IV

Liver metabolism responsible for this

Question 2

Phase 1

Answer 2

Oxidation, reduction, hydrolysis
cytochrome P450 enzymes (CYPs)
Mostly adds hydroxyl
Lots of energy

Question 3

Phase 2

Answer 3

Conjugation
glutathione S-transferases, sulfotransferases, UDP glucuronic acid transferases
Lower in energy

Question 4

CYP3A4

Answer 4

Most abundant
Acetaminophen, lovastatin, felodipine
Many adverse reaction involve inhibition of this

Question 5

CYP2C9/19

Answer 5

Second most common

Question 6

CYP2D6

Answer 6

Only 4% of total content but 30% of drug metabolism
Highly polymorphic
Tamoxifen

Question 7

Conjugation

Answer 7

Formation of metabolite with increased molecular mass,..biological activity terminated

Question 8

Glutathione S transferases

Answer 8

Protect cells from oxidative damage by transferring glutathione to electrophils
Lack of glutathione leads to oxidative damage and liver failure
IMportant in acetaminophen and anti cancer drug resistance
Affected by alcohol abuse

Question 9

UDP-glucuronosyl transferases

Answer 9

Billirubin homeostasis

Billirubin peaks 3-4 days after born because of delayed expression of enzyme

Question 10

N-acetyl transferases

Answer 10

Metabolize drugs with aromatic amine or hydrazine

Question 11

Thiopurine methyltransferase

Answer 11

Methylation of thiopurine drug 6-mercaptopurine

Question 12

6-mercaptopruine used to treat

Answer 12

Leukemia and Crohn’s

Question 13

Acetaminophen phase 1 and 2

Answer 13

Could be glucuronidated or sulfated during phase 1
Creates toxic metabolite
Glutathione S transferase will add glutathione and make neutral

If alcohol present, increases CYP2E1 and decreases glutathione and increases metabolite that destroys hepatocytes

Question 14

Antidote to acetominophen poisoning

Answer 14

N-acetylcysteine helps body make more glutathione

Question 15

Phase 3 metabollism

Answer 15

Transport of drugs into or out of cells

Question 16

Hepatic metabolism

Answer 16

Transport into hepatocytes and excretion into bile

Question 17

Oral bioavailability

Answer 17

Transport into enterocytes and excretion into intestinal lumen

Question 18

Renal clearance

Answer 18

Transport into proximal tubular cells

Excreted into tubular lumen

Question 19

BBB

Answer 19

Restricts entry of drugs to CNS

Question 20

MDR1

Answer 20

Luminally expressed efflux transporter in the GI, liver, brain, kidney
Maintains low concentrations of substrates
Upregulated in tumor cells to decrease effect of chemo
Used in the kidney and liver to get into urine and bile

Question 21

Prodrug

Answer 21

Must be cleaved in order to become a product
Product could have higher potency than the original so overactivation of enzyme that breaks down (cytochrome p450) could lead to overdose

Question 22

6-mercaptopurine

Answer 22

Prodrug used to treat leukemia and Crohn’s

TPMT will inhibit incorporation of the drug into DNA (needed to work)

Fewer TMPT mean maybe too much into DNA

Question 23

Tamoxifen

Answer 23

Needs to be cleaved by CYP3A4/5 and CYP2D6 in order to become endoxifen active form

Could go through either enzyme first/second

Question 24

Drug activation of CYP450s

Answer 24

Activates nuclear receptor PXR…has longer effect than inhibiton

Question 25

Inhibition of CYP450s

Answer 25

Drug binds to the enzyme

Question 26

Enzyme induction typially due to

Answer 26

Amount of enzyme made in the liver | Peak 4-14 days and back to normal in 1-3 weeks

Question 27

Inducing CYP450s will cause

Answer 27

A decrease in drug effect

Question 28

St Johns Wort drug interaction

Answer 28

St Johns wort increases expression of CYP3A4 activity...this breaks down felodipine normally so if you're taking St Johns Worst and Felodipine, concentration of felodipine will be lower

Question 29

In inhibition of drug metabolism

Answer 29

Efficiacy of drug decreased (think prodrugs) | Toxicity of parent drug increased

Question 30

Stimulation of drug metabolism

Answer 30

Efficacy of drug decreased and toxicity of the metabolite is increased

Question 31

Lovastatin

Answer 31

``` Targets hepatocyte in the liver Metabolized by CYP3A4 Requires transporter SLCO1B1 Adverse effects include myopathy Symptoms include muscle pain ```

Question 32

What increases lovastatin concentrations

Answer 32

CYP3A4 inhibitors (grapefruit juice, intraconozole)

Question 33

Itraconzole/felodipine interaction

Answer 33

Intraconazole used to treat fungal infections...inhibits CYP3A4...Felodipine for high blood pressure...Felodipine is CYP3A4 substrate...adverse effects associated with low blood pressure (headaches) Will kick up HR

Question 34

Grapefruit juice

Answer 34

Inhibits CYP3A4 and can increase felodipine and statin concentrations

Question 35

St Johns wort

Answer 35

Increases CYP3A4 expression and can increase clearance of drugs

Question 36

Polymorphisms can effect

Answer 36

Clearance of drugs

Question 37

CYP2D6 polymorphisms

Answer 37

Poor metabolizers IM metabolizers Ultrarapid metabolizers Extensive (normal) metabolizers

Question 38

CYP2D6 and tamoxifen

Answer 38

Women with deficient CYP2D6 are at heightened risk of tx falure...can't convert to endoxifen Amplichip can help test for this undecided whether this actually help

Question 39

Polymorphism in Thiopurine methyltrasnferase

Answer 39

problems with 6-mercaptopurine response If wild/wild - then decreased toxicity but increased risk of relapse...higher Intracell concentration If mutant/mutant - increased myelosupprresion and increased risk of secondary cancer...lower intracell concenrtaton

Question 40

Statins and SCLO1B1

Answer 40

If transport is low, then lovastatin is poorly metabolized and systemic circulation high...means that increased risk of myopathy

Question 41

Age and drug metabolism

Answer 41

Less than 1 month and older than 65 are lower (decreased CYP activity) Elderly also have decreased renal funciton and decreased hepatic blood flow

Question 42

Gender and drug metabo

Answer 42

Females have greater risk of developing abnormal response...due to lots of things included phase 1,2, and transporter

Question 43

Two enzymes higher in females

Answer 43

CYP2D6 and CYP3a

Question 44

Liver dz and drug metabolism

Answer 44

Cytochrome P450 decreases as liver function decrewases | Glucuronidation is less affected but can be affected in severe cases

Question 45

Obesity and drug metabolism

Answer 45

Often develop fatty liver Increase CYP2E1, decrease CYP3A, and increase UDPGT Could impact volume of distribution and clearance

Question 46

Felodipine important

Answer 46

CYP3A4 substrate

Question 47

Iraconazole important

Answer 47

CYP3A4 inhibitor

Question 48

6-mercaptopurine important

Answer 48

TPMP substrate and prodrug

Question 49

Lovastatin important

Answer 49

CYP3A4 substrate and SCLO1B1 substrate

Question 50

St John's Wort important

Answer 50

CYP3A4 inducer

Question 51

Tamoxifen important

Answer 51

CYP2D6 substrate and a prodrug