Lecture 7: Metabolism

Question 1

CYP450 induction mechanism

Answer 1

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

Question 2

induction cross-talk

Answer 2

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

Question 3

Inducers cause a wider array of drug interactions than inhibitors

Answer 3

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

Question 4

Autoinduction

Answer 4

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

Question 5

Consequences of metabolisms

Answer 5

1. active to inactive
2. inactive to active
3. active to reactive

Question 6

CYP1A1/2 substrates

Answer 6

-PAHs
-arylamines
-nitrosamines

Question 7

CYP1A1/2

Answer 7

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

Question 8

CYP2 family

Answer 8

-2A6
-2B6
-2C9/8

-lots more substrates

Question 9

CYP2C subfamily

Answer 9

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

Question 10

CYP2D6

Answer 10

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

Question 11

CYP2D6 metabolism

Answer 11

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

Question 12

CYP2D6 inhibition

Answer 12

-fluoxetine
-quinidine
-bupropion

Question 13

CYP3A4

Answer 13

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

Question 14

CYP3A4

Answer 14

-50% of drugs
-low specificity

Question 16

Codeine and children

Answer 16

-fast metabolizers
-form more morphine
-respiratory depression

Question 17

CYP3A4 substrates

Answer 17

-midazolam
-indinavir

Question 18

CYP3A4 inhibitors

Answer 18

-ritonavir
-ketoconazole

Question 19

CYP3A4 inducers

Answer 19

-rifampin
-St. John’s wort

Question 20

CYP2D6 substrates

Answer 20

-codeine
-fluoxetine

Question 21

CYP2D6 inhibitors

Answer 21

-fluoxetine
-quinidine

Question 22

CYP2D6 inducers

Answer 22

??

Question 23

CYP2C9 substrates

Answer 23

-S-warfarin
-ibuprofen

Question 24

CYP2C9 inhibitors

Answer 24

-fluconazole
-amiodarone

Question 25

CYP2C9 inducers

Answer 25

-rifampin -secobarbital

Question 26

Phase I enzymes

Answer 26

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

Question 27

alcohol dehydrogenase (ADH)

Answer 27

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

Question 28

Phase II metabolism

Answer 28

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

Question 29

Increased solubility

Answer 29

increased urinary excretion

Question 30

Phase II enzymes

Answer 30

-UGT -GST -NAT -TPMT -SULT

Question 31

UGT

Answer 31

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

Question 32

UGT reaction

Answer 32

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

Question 33

How to reduce glucuronidation of drug

Answer 33

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

Question 34

UGT and CYP450

Answer 34

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

Question 35

sulfotransferases (SULT)

Answer 35

-drug + PAPS --> sulfated drug + PAP

Question 36

GST

Answer 36

-glutathione conjugation

Question 37

methyltransferases

Answer 37

-O,N,S methylation

Question 38

N-acetyltransferase (NAT)

Answer 38

add =O -N,O carcinogen activation