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Foundations 5 > Drug metabolism > Flashcards

Drug metabolism Flashcards

1
Q

First pass effect dosing

A

Need higher concentration orally vs. IV

Liver metabolism responsible for this

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2
Q

Phase 1

A

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

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3
Q

Phase 2

A

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

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4
Q

CYP3A4

A

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

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5
Q

CYP2C9/19

A

Second most common

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6
Q

CYP2D6

A

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

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7
Q

Conjugation

A

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

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8
Q

Glutathione S transferases

A

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

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9
Q

UDP-glucuronosyl transferases

A

Billirubin homeostasis

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

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10
Q

N-acetyl transferases

A

Metabolize drugs with aromatic amine or hydrazine

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11
Q

Thiopurine methyltransferase

A

Methylation of thiopurine drug 6-mercaptopurine

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12
Q

6-mercaptopruine used to treat

A

Leukemia and Crohn’s

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13
Q

Acetaminophen phase 1 and 2

A

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

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14
Q

Antidote to acetominophen poisoning

A

N-acetylcysteine helps body make more glutathione

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15
Q

Phase 3 metabollism

A

Transport of drugs into or out of cells

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16
Q

Hepatic metabolism

A

Transport into hepatocytes and excretion into bile

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17
Q

Oral bioavailability

A

Transport into enterocytes and excretion into intestinal lumen

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18
Q

Renal clearance

A

Transport into proximal tubular cells

Excreted into tubular lumen

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19
Q

BBB

A

Restricts entry of drugs to CNS

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20
Q

MDR1

A

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

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21
Q

Prodrug

A

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

22
Q

6-mercaptopurine

A

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

23
Q

Tamoxifen

A

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

Could go through either enzyme first/second

24
Q

Drug activation of CYP450s

A

Activates nuclear receptor PXR…has longer effect than inhibiton

25
Q

Inhibition of CYP450s

A

Drug binds to the enzyme

26
Q

Enzyme induction typially due to

A

Amount of enzyme made in the liver

Peak 4-14 days and back to normal in 1-3 weeks

27
Q

Inducing CYP450s will cause

A

A decrease in drug effect

28
Q

St Johns Wort drug interaction

A

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

29
Q

In inhibition of drug metabolism

A

Efficiacy of drug decreased (think prodrugs)

Toxicity of parent drug increased

30
Q

Stimulation of drug metabolism

A

Efficacy of drug decreased and toxicity of the metabolite is increased

31
Q

Lovastatin

A 
Targets hepatocyte in the liver 
Metabolized by CYP3A4 
Requires transporter SLCO1B1 
Adverse effects include myopathy 
Symptoms include muscle pain
32
Q

What increases lovastatin concentrations

A

CYP3A4 inhibitors (grapefruit juice, intraconozole)

33
Q

Itraconzole/felodipine interaction

A

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

34
Q

Grapefruit juice

A

Inhibits CYP3A4 and can increase felodipine and statin concentrations

35
Q

St Johns wort

A

Increases CYP3A4 expression and can increase clearance of drugs

36
Q

Polymorphisms can effect

A

Clearance of drugs

37
Q

CYP2D6 polymorphisms

A

Poor metabolizers
IM metabolizers
Ultrarapid metabolizers
Extensive (normal) metabolizers

38
Q

CYP2D6 and tamoxifen

A

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

39
Q

Polymorphism in Thiopurine methyltrasnferase

A

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

40
Q

Statins and SCLO1B1

A

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

41
Q

Age and drug metabolism

A

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

42
Q

Gender and drug metabo

A

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

43
Q

Two enzymes higher in females

A

CYP2D6 and CYP3a

44
Q

Liver dz and drug metabolism

A

Cytochrome P450 decreases as liver function decrewases

Glucuronidation is less affected but can be affected in severe cases

45
Q

Obesity and drug metabolism

A

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

46
Q

Felodipine important

A

CYP3A4 substrate

47
Q

Iraconazole important

A

CYP3A4 inhibitor

48
Q

6-mercaptopurine important

A

TPMP substrate and prodrug

49
Q

Lovastatin important

A

CYP3A4 substrate and SCLO1B1 substrate

50
Q

St John’s Wort important

A

CYP3A4 inducer

51
Q

Tamoxifen important

A

CYP2D6 substrate and a prodrug

Foundations 5 (13 decks)

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