Lecture 7: Metabolism Flashcards

1
Q

CYP450 induction mechanism

A

-drugs bind to CYP TFs
-increase transcription
-increase CYP450
-increase metabolism

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2
Q

induction cross-talk

A

-many substrates can turn on different CYPs
-alter metabolism of a LOT of drugs

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3
Q

Inducers cause a wider array of drug interactions than inhibitors

A

-reacts with PXR
-doesnt have to interact with CYP directly

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4
Q

Autoinduction

A

-inducer [drug] can activate own metabolism
-concentration decreases with same dose

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5
Q

Consequences of metabolisms

A
  1. active to inactive
  2. inactive to active
  3. active to reactive
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6
Q

CYP1A1/2 substrates

A

-PAHs
-arylamines
-nitrosamines

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7
Q

CYP1A1/2

A

-planar binding site
-only binds flat (planar) molecules

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8
Q

CYP2 family

A

-2A6
-2B6
-2C9/8

-lots more substrates

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9
Q

CYP2C subfamily

A

-metabolizes 25% of drugs
-bigger binding pocket
-CYP2C9 most important

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10
Q

CYP2D6

A

-metabolizes 20% drugs
-small amounts in body
-weakly inducible

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11
Q

CYP2D6 metabolism

A

-lipophilic amines
-ion-pair interactions
-cardiovascular drugs, B blockers, antipsychotics, SSRIs etc

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12
Q

CYP2D6 inhibition

A

-fluoxetine
-quinidine
-bupropion

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13
Q

CYP3A4

A

-biggEST pocket
-inducer increases metabolism of ALL substrates
-inhibitor will not compete with all substrates

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14
Q

CYP3A4

A

-50% of drugs
-low specificity

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15
Q
A
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16
Q

Codeine and children

A

-fast metabolizers
-form more morphine
-respiratory depression

17
Q

CYP3A4 substrates

A

-midazolam
-indinavir

18
Q

CYP3A4 inhibitors

A

-ritonavir
-ketoconazole

19
Q

CYP3A4 inducers

A

-rifampin
-St. John’s wort

20
Q

CYP2D6 substrates

A

-codeine
-fluoxetine

21
Q

CYP2D6 inhibitors

A

-fluoxetine
-quinidine

22
Q

CYP2D6 inducers

A

??

23
Q

CYP2C9 substrates

A

-S-warfarin
-ibuprofen

24
Q

CYP2C9 inhibitors

A

-fluconazole
-amiodarone

25
Q

CYP2C9 inducers

A

-rifampin
-secobarbital

26
Q

Phase I enzymes

A

-FMO
-ADH
-MAO
-Esterase
-amidase
-epoxide hydrolase

27
Q

alcohol dehydrogenase (ADH)

A

-metabolizes ethanol to acetaldehyde
-vomiting sick
-inhibited by disulfram to treat

28
Q

Phase II metabolism

A

-couple drug with conjugates
-polar groups
-increase solubility
=increase urinary excretion
-inactivate compounds usually

29
Q

Increased solubility

A

increased urinary excretion

30
Q

Phase II enzymes

A

-UGT
-GST
-NAT
-TPMT
-SULT

31
Q

UGT

A

-dominant phase II enzyme
-readily available supply of glucose and UTP in liver
-many functional groups can form conjugates

32
Q

UGT reaction

A

-conjugates glucuronic acid component of UDPGA to drug
-UDPGA + drug –> glucuronide-conjugated drug + UDP

33
Q

How to reduce glucuronidation of drug

A

-inhibit enzyme
-reduce amount of enzyme produced
-reduce amount of cosubstrate

34
Q

UGT and CYP450

A

-right next to each other on membrane of ER
-phase I metabolite travels short distance to UGT

35
Q

sulfotransferases (SULT)

A

-drug + PAPS –> sulfated drug + PAP

36
Q

GST

A

-glutathione conjugation

37
Q

methyltransferases

A

-O,N,S methylation

38
Q

N-acetyltransferase (NAT)

A

add =O
-N,O carcinogen activation

39
Q
A