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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
N-glucuronides of aromatic amines are very labile and suspected__________
CARCINOGENS
26
This drug was shown to have a potentially fatal interaction with cerivastatin
GEMFIBROZIL
27
Which enzyme does gemfibrozil glucuronide inhibit?
2C8
28
This drug is a probe for 2C8 activity
Paclitaxel
29
Gemfibrozil glucuronide is a [CONCENTRATION/TIME] dependent INHIBITOR of 2C8
TIME
30
This chemo agent is metabolized by 2C8, and thus co-administration with gemfibrozil (glucuronide) can cause issues
Paclitaxel
31
Studies with gemfibrozil glucuronide separated paclitaxel and gemfibrozil glucuronide administration by ____ minutes (as well as administering with NADPH) to show the DDI?
30
32
Gemfibrozil is a ____-____ INHIBITOR of 2C8
MECHANISM-BASED
33
What is the half-life of gemfibrozil?
1 hour
34
How long after a dose of gemfibrozil can the effect on repaglinide last?
12 hours
35
T/F: | Gemfibrozil glucuronide's INHIBITION of 2C8 is highest at the peak concentration of the glucuronide
FALSE | Time Dependent
36
Total-Direct = _____ bilirubin
INDIRECT
37
By calculating direct and indirect bilirubin, we can determine activity levels of this enzyme
UGT1A1
38
UGT1A1* ____ is most common loss of function allele? | [10-33% of Caucasians have this mutation]
28
39
Elevation in [CONJUGATED/UNCONJUGATED] bilirubin leads to jaundice
UNCONJUGATED
40
______syndrome refers to having more unconjugated bilirubin, such as in a patient with UGT1A1*28
GILBERT'S | [typically benign but van have major consequences as ADE]
41
T/F: | Gilbert's syndrome is often harmless
TRUE | [until DDIs]
42
This type of enzyme creates SN-38 from irinotecan
CARBOXYLESTERASE
43
Infants with_______ typically have profound elevated levels of bilirubin
CRIGLER-NAJJAR
44
SN-38-glucuronide is [ACTIVE/INACTIVE]
INACTIVE
45
Irinotecan is a prodrug metabolized to the active drug ________ by a carboxylesterase?
SN-38
46
A faulty UGT1A1 allele will lead to elevated levels of _______ in patients taking irinotecan, which can lead to overdose?
SN-38
47
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.
NEUTROPENIA
48
This OTC will induce UGT1A1?
SJW
49
This HIV medication should have its dose INCREASED when given with rifampin
Raltegravir
50
Raltegravir is specifically mentioned to have a DOSE INCREASE when given with _____ due to UGT1A1 DDIs
Rifampin
51
Rifampin/Raltegravir is a noted interaction due effects on this enzyme?
UGT1A1
52
T/F: | When we increased irinotecan dose to give the same SN-38 levels we still saw less efficacy
TRUE
53
Rifampin a strong INDUCER of UGT1A1, reduces plasma concentrations of Isentress, AKA_____
Raltegravir
54
Glucoronidation makes metabolites {MORE/LESS] polar
MORE
55
Smaller glucuronidated molecules are excreted in urine, while larger ones are excreted in_________
Bile
56
UGT1 is located on chromosome _____
2
57
UGT2 is located on chromosome______
4
58
UGT activity [INCREASES/DECREASES] in pregnancy?
INCREASES
59
This active opioid is a result of glucoronidation metabolism?
Morphine-6-glucuronide
60
This drug, when glucuronidated, becomes a 2C8 INHIBITOR?
Gemfibrozil
61
___-_____disease involves progressive liver disease, often fatal. This involves a lack/reduction of UGT1A1 activity
Crigler-najjar
62
SN-38-glucuronide is [ACTIVE/INACTIVE]
INACTIVE
63
T/F: | When we increased irinotecan dose to give the same SN-38 levels, we still saw LESS efficacy
TRUE
64
VPA [INCREASES/DECREASES] lamotrigine. | While lamotrigine [INCREASES/DECREASES] VPA concentration
INCREASES DECREASES
65
Patients on UGT inducers might be at higher risk of GI side effects when on this transplant drug?
MPA
66
What is UGT?
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
Where is UGT expressed?
Highest in GI & Liver | Also in kidneys, brain, lung
68
Why is UGT not a a big DDI culprit? (3)
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
Codeine clearance pathways?
1. 50-70% via UGT 2B7 = glucuronide 2. 0-15% via 2D6 = morphine 3. 10 -15% via 3A4 = norcodeine
70
UGT variability in AGE
Low but VERY variable UGT activity in INFANTS
71
UGT variability in GENDER
Males UGT >> Females UGT
72
UGT variability in PREGNANCY
UGT INCREASED during pregnancy
73
Lamotrigine + Valproate DDI
``` Lamotrigine = 2B7 SUBSTRATE & INDUCER VPA = 2B& SUBSTRATE & INHIBITOR ``` Lamotrigine induces UGT 2B7 = INCREASED CL of VPA VPA inhibits UGT 2B7 = DECREASES CL of lamotrigine
74
MPA + Rifampin DDI
``` 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
MPA + PHT DDI
``` PHT = INDUCER MPA = UGT SUBSTRATE ``` same interaction as MPA + Rifampin
76
Glucuronide metabolites are important b/c they can be.....(3)
1. active 2. toxic 3. inhibitors
77
Morphine glucoronidation
Morphine-6-glucuronide = ACTIVE; greater analgesic potency than morphine itself Morphine-3-glucuronide = INACTIVE
78
Ezetimibe glucoronidation
Conjugated metabolite = ACTIVE; undergoes enterohepatic recycling = long duration of action
79
Acyl glucuronides
Generally considered toxic; undergoes spontaneous hydrolysis of -COOH group; covalently binds tissues Associated with: anaphylaxis/hypersensitivity, hepatotoxicity SJS
80
Drugs that get metabolized to TOXIC N-glucuronides (3 classes that are aromatic amines!)
1. antipsychotics 2. antihistamines 3. TCAs
81
What single drug was withdrawn from the market b/c its acyl glucuronide caused anaphylaxis?
Zomepirac (NSAID)
82
Gemfibrozil + cerivastatin DDI
Both gemfibrozil and its glucuronide metabolite are INHIBITORS of 2C8. The metabolite is much MORE potent inhibitor. Cause INCREASED [cerivastatin] = rhabdo case reports
83
How did they find out gemfibrozil-glucuronide was a 2C8 inhibitor?
Gemfibrozil + paclitaxel (2C8 probe); difference in pre-vs-post incubation
84
Gemfibrozil + repaglinide DDI
Gemfibrozil and metabolite both INHIBIT 2C8 CL of repaglinide
85
How long does gemfibrozil's glucuronide affect 2C8?
At lease 12 hours post gemfibrozil dose Gemfibrozil = time-dependent INHIBITOR; likely MBI
86
Clopidogrel's glucuronide inhibits what?
2C8 = STONG MBI based inhibition
87
UGT1A1 polymorphisms
``` 1* = wild-type 28* = reduced activity, found in some whites *6 = reduced activity found in Asians ```
88
UGT1A1 polymorphism is associated with what disease?
Gilbert's disease/syndrome
89
egIrinotecan + UGT1A1 polymorphisms
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
Drugs that INHIBIT UGT1A1
1. Protease inhibitors: atazanavir, indinavir | 2. TKIs: erlotinib, nilotinik, panzopanib, sorafenib
91
Raltegravir + atazanavir DDI
Atazanavir INHIBITS UGT1A1 = INCREASED [Raltegravir]
92
Efavirenz vs rifampin?
Efavirenz is a much more consistent INDUCER than rifampin per FDA
93
Substrates of UGT1A1 (4)
1. etoposide 2. ezetimibe 3. irinotecan/SN-38 4. Raltegravir
94
Lifestyle inducer of 1A1
Smoking

PCEUT 510 (12 decks)

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