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PCEUT 510 > #2 Interactions Involving UGTs > Flashcards

#2 Interactions Involving UGTs Flashcards

1
Q

UGTs are phase ____ enzymes?

A

II

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2
Q

T/F:

Glucoronidation RXNs occur in the intestine, kidney, brain and lung (not just the liver)

A

TRUE

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3
Q

Glucoronidation makes metabolites [MORE/LESS] polar?

A

MORE

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4
Q

When a drug is Glucuronidate it becomes more hydrophilic and will require______ to get out of the cell?

A

TRANSPORT

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5
Q

T/F:

Glucuronidated products are ALWAYS inactive?

A

FALSE
Glucuronidated products are NOT always inactive.
Active products have PD effects, toxic metabolites (can bind to enzymes),and PK effects like enzyme inhibition

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6
Q

Smaller Glucuronidated molecules are excreted in urine, while larger ones are excreted in _______?

A

BILE

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7
Q

The clearance of codeine is dominated by UGT2B7, but the pharmacological activity is controlled primarily by CYP2D.
What drug?

A

Codeine

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8
Q

[MALES/FEMALES] have more UGT activity?

A

MALES

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9
Q

UGT activity [INCREASES/DECREASES] in pregnancy

A

INCREASES

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10
Q

Both IRREVERSIBLE INHIBITION & INDUCTION are ______dependent.

A

CONCENTRATION

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11
Q

Lamotrigine & Valproate are both substrates of what metabolic phase II enzyme?

A

UGT2B7

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12
Q

Valproate [INHIBITS/INDUCES] lamotrigine conjugation by 2B7

A

INHIBITS

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13
Q

Lamotrigine [INHIBITS/INDUCES] valproate conjugation (1A6/1A9)

A

INDUCES

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14
Q

How does Rifampin affect Mycophenolate concentrations?

A

INCREASES CL of mycophenolic acid = DECREASE in levels
However, Mycophenolic acid acyl glucuronide AUC INCREASED 130% (Because of enterohepatic recycling).
This could put people at risk for more GI side effects

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15
Q

Raltegravir and SN-38 are both substrates of what enzyme?

A

UGT1A1

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16
Q

Atazanavir, Gefitinib, Nilotinib, Pazopanib, Sorfenib are all INHIBITORS of what phase II enzyme?

A

UGT1A1

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17
Q

This pharmacodynamically active opioid is a result of glucoronidation metabolism?

A

morphine-6-glucuronide

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18
Q

What glucuronide toxic metabolite forms protein adducts?

A

acyl glucuronides

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19
Q

This drug, when glucuronidated, becomes a 2C8 INHIBITOR?

A

Gemfibrozil

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20
Q

Morphine-[3/6]-glucuronide is the more common product?

A

3 (and is inactive)

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21
Q

T/F:

M6G is actually more potent than morphine

A

TRUE

[40-60 X more potent than morphine]

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22
Q

Which UGT enzyme metabolizes about 60% of the morphine dose to M3G?

A

UGT2B7

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23
Q

Which drug undergoes enterohepatic recycling of tis active phenolic metabolite?

A

ezetimibe

phenol is UGT enzyme produced

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24
Q

Which UGT enzyme metabolizes about 5-10% of the dose to the highly active M6G?

A

UGT1B1

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25
Q

N-glucuronides of aromatic amines are very labile and suspected__________

A

CARCINOGENS

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26
Q

This drug was shown to have a potentially fatal interaction with cerivastatin

A

GEMFIBROZIL

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27
Q

Which enzyme does gemfibrozil glucuronide inhibit?

A

2C8

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28
Q

This drug is a probe for 2C8 activity

A

Paclitaxel

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29
Q

Gemfibrozil glucuronide is a [CONCENTRATION/TIME] dependent INHIBITOR of 2C8

A

TIME

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30
Q

This chemo agent is metabolized by 2C8, and thus co-administration with gemfibrozil (glucuronide) can cause issues

A

Paclitaxel

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31
Q

Studies with gemfibrozil glucuronide separated paclitaxel and gemfibrozil glucuronide administration by ____ minutes (as well as administering with NADPH) to show the DDI?

A

30

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32
Q

Gemfibrozil is a ____-____ INHIBITOR of 2C8

A

MECHANISM-BASED

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33
Q

What is the half-life of gemfibrozil?

A

1 hour

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34
Q

How long after a dose of gemfibrozil can the effect on repaglinide last?

A

12 hours

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35
Q

T/F:

Gemfibrozil glucuronide’s INHIBITION of 2C8 is highest at the peak concentration of the glucuronide

A

FALSE

Time Dependent

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36
Q

Total-Direct = _____ bilirubin

A

INDIRECT

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37
Q

By calculating direct and indirect bilirubin, we can determine activity levels of this enzyme

A

UGT1A1

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38
Q

UGT1A1* ____ is most common loss of function allele?

[10-33% of Caucasians have this mutation]

39
Q

Elevation in [CONJUGATED/UNCONJUGATED] bilirubin leads to jaundice

A

UNCONJUGATED

40
Q

______syndrome refers to having more unconjugated bilirubin, such as in a patient with UGT1A1*28

A

GILBERT’S

[typically benign but van have major consequences as ADE]

41
Q

T/F:

Gilbert’s syndrome is often harmless

A

TRUE

[until DDIs]

42
Q

This type of enzyme creates SN-38 from irinotecan

A

CARBOXYLESTERASE

43
Q

Infants with_______ typically have profound elevated levels of bilirubin

A

CRIGLER-NAJJAR

44
Q

SN-38-glucuronide is [ACTIVE/INACTIVE]

45
Q

Irinotecan is a prodrug metabolized to the active drug ________ by a carboxylesterase?

46
Q

A faulty UGT1A1 allele will lead to elevated levels of _______ in patients taking irinotecan, which can lead to overdose?

47
Q

A faulty UGT1A1 allele(such as *28) will lead to elevated levels of SN-38 in patients taking irinotecan, which can lead to overdose. ________ would be the most common & alarming symptom.

A

NEUTROPENIA

48
Q

This OTC will induce UGT1A1?

49
Q

This HIV medication should have its dose INCREASED when given with rifampin

A

Raltegravir

50
Q

Raltegravir is specifically mentioned to have a DOSE INCREASE when given with _____ due to UGT1A1 DDIs

51
Q

Rifampin/Raltegravir is a noted interaction due effects on this enzyme?

52
Q

T/F:

When we increased irinotecan dose to give the same SN-38 levels we still saw less efficacy

53
Q

Rifampin a strong INDUCER of UGT1A1, reduces plasma concentrations of Isentress, AKA_____

A

Raltegravir

54
Q

Glucoronidation makes metabolites {MORE/LESS] polar

55
Q

Smaller glucuronidated molecules are excreted in urine, while larger ones are excreted in_________

56
Q

UGT1 is located on chromosome _____

57
Q

UGT2 is located on chromosome______

58
Q

UGT activity [INCREASES/DECREASES] in pregnancy?

59
Q

This active opioid is a result of glucoronidation metabolism?

A

Morphine-6-glucuronide

60
Q

This drug, when glucuronidated, becomes a 2C8 INHIBITOR?

A

Gemfibrozil

61
Q

___-_____disease involves progressive liver disease, often fatal. This involves a lack/reduction of UGT1A1 activity

A

Crigler-najjar

62
Q

SN-38-glucuronide is [ACTIVE/INACTIVE]

63
Q

T/F:

When we increased irinotecan dose to give the same SN-38 levels, we still saw LESS efficacy

64
Q

VPA [INCREASES/DECREASES] lamotrigine.

While lamotrigine [INCREASES/DECREASES] VPA concentration

A

INCREASES

DECREASES

65
Q

Patients on UGT inducers might be at higher risk of GI side effects when on this transplant drug?

66
Q

What is UGT?

A
  1. UDP-glucuronosyltransferase
  2. MOST abundant of the Phase II enzymes
  3. Facilitates glucoronidation = nucleophilic substrates become more polarized = easier to excrete
  4. 19 isozymes
67
Q

Where is UGT expressed?

A

Highest in GI & Liver

Also in kidneys, brain, lung

68
Q

Why is UGT not a a big DDI culprit? (3)

A
  1. Few (known) inhibitors of UGT
  2. Substrates overlap b/n various isozymes, so f(m) is usually <0.5 for a single UGT
  3. Few clinical studies
69
Q

Codeine clearance pathways?

A
  1. 50-70% via UGT 2B7 = glucuronide
  2. 0-15% via 2D6 = morphine
  3. 10 -15% via 3A4 = norcodeine
70
Q

UGT variability in AGE

A

Low but VERY variable UGT activity in INFANTS

71
Q

UGT variability in GENDER

A

Males UGT&raquo_space; Females UGT

72
Q

UGT variability in PREGNANCY

A

UGT INCREASED during pregnancy

73
Q

Lamotrigine + Valproate DDI

A 
Lamotrigine = 2B7 SUBSTRATE &amp; INDUCER 
VPA = 2B&amp; SUBSTRATE &amp; INHIBITOR

Lamotrigine induces UGT 2B7 = INCREASED CL of VPA

VPA inhibits UGT 2B7 = DECREASES CL of lamotrigine

74
Q

MPA + Rifampin DDI

A 
Rifampin = INDUCER 
MPA = SUBSTRATE; Glucoronidation is important for enterohepatic recycling

INCREASED UGT activity = DECREASED [MPA] but INCREASED diarrhea b/c you are delivering more drug to the gut

75
Q

MPA + PHT DDI

A 
PHT = INDUCER 
MPA = UGT SUBSTRATE

same interaction as MPA + Rifampin

76
Q

Glucuronide metabolites are important b/c they can be…..(3)

A
  1. active
  2. toxic
  3. inhibitors
77
Q

Morphine glucoronidation

A

Morphine-6-glucuronide = ACTIVE; greater analgesic potency than morphine itself

Morphine-3-glucuronide = INACTIVE

78
Q

Ezetimibe glucoronidation

A

Conjugated metabolite = ACTIVE; undergoes enterohepatic recycling = long duration of action

79
Q

Acyl glucuronides

A

Generally considered toxic; undergoes spontaneous hydrolysis of -COOH group; covalently binds tissues

Associated with: anaphylaxis/hypersensitivity, hepatotoxicity
SJS

80
Q

Drugs that get metabolized to TOXIC N-glucuronides (3 classes that are aromatic amines!)

A
  1. antipsychotics
  2. antihistamines
  3. TCAs
81
Q

What single drug was withdrawn from the market b/c its acyl glucuronide caused anaphylaxis?

A

Zomepirac (NSAID)

82
Q

Gemfibrozil + cerivastatin DDI

A

Both gemfibrozil and its glucuronide metabolite are INHIBITORS of 2C8.
The metabolite is much MORE potent inhibitor.

Cause INCREASED [cerivastatin] = rhabdo case reports

83
Q

How did they find out gemfibrozil-glucuronide was a 2C8 inhibitor?

A

Gemfibrozil + paclitaxel (2C8 probe); difference in pre-vs-post incubation

84
Q

Gemfibrozil + repaglinide DDI

A

Gemfibrozil and metabolite both INHIBIT 2C8 CL of repaglinide

85
Q

How long does gemfibrozil’s glucuronide affect 2C8?

A

At lease 12 hours post gemfibrozil dose

Gemfibrozil = time-dependent INHIBITOR; likely MBI

86
Q

Clopidogrel’s glucuronide inhibits what?

A

2C8 = STONG MBI based inhibition

87
Q

UGT1A1 polymorphisms

A 
1* = wild-type 
28* = reduced activity, found in some whites 
*6 = reduced activity found in Asians
88
Q

UGT1A1 polymorphism is associated with what disease?

A

Gilbert’s disease/syndrome

89
Q

egIrinotecan + UGT1A1 polymorphisms

A

Irinotecan is conjugated by UGT1A1 = active metabolite SN-38

SN-38 is conjugated by UGT as well = inactive metabolite; undergoes enterohepatic recycling

DECREASED 1A1 activity = INCREASED [irinotecan] = INCREASED toxicities, namely NEUTROPENIA

90
Q

Drugs that INHIBIT UGT1A1

A
  1. Protease inhibitors: atazanavir, indinavir

2. TKIs: erlotinib, nilotinik, panzopanib, sorafenib

91
Q

Raltegravir + atazanavir DDI

A

Atazanavir INHIBITS UGT1A1 = INCREASED [Raltegravir]

92
Q

Efavirenz vs rifampin?

A

Efavirenz is a much more consistent INDUCER than rifampin per FDA

93
Q

Substrates of UGT1A1 (4)

A
  1. etoposide
  2. ezetimibe
  3. irinotecan/SN-38
  4. Raltegravir
94
Q

Lifestyle inducer of 1A1

PCEUT 510 (12 decks)

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