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Med Chem > Lecture 4 (Drug Metabolism) > Flashcards

Lecture 4 (Drug Metabolism) Flashcards

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1
Q

Main site in body for drug metabolism?

A

liver

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2
Q

Liver is the site of ???

A

1st pass metabolism

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3
Q

Where else can drugs be metabolized in the body?

A
  • secretion into bile
  • elimination in feces
  • kidneys (filter blood)
  • lungs (exhale drugs)
  • intestinal gut flora
  • skin and other organs
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4
Q

Very hydrophilic drugs will get excreted ____

A

unchanged

they are already water soluble

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5
Q

Lipophilic drugs are usually ______

A

metabolized

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6
Q

Why do lipophilic drugs tend to be in the body longer than hydrophilic drugs?

A

1 - they need to be metabolized

2- lipophilic drugs can bind to proteins that are distributed in fatty tissues

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7
Q

lipophilic drugs generally avoid excretion by _____

A

kidney

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8
Q

goal of drug metabolism?

A

chemically modify (metabolize) lipophilic drugs to increase their water solubility so they can be excreted by the kidney

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9
Q

Phase 1 metabolism?

A

drug becomes modified drug by:
-adding/exposing functional groups to make it more water soluble

oxidation (most common)
hydrolysis
reduction

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10
Q

Phase 2 metabolism?

A

biosynthetic conjugation

modified drug transforms to drug-conjugated

Glucuronidation
Acetylation (glutathione)
Sulfation

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11
Q

There are typically several routes of metabolism - why is this a good thing?

A

it is good that there is more than 1 route because if something affects one route - the drug will not accumulate in the body and pose a risk of potential toxicity

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12
Q

cytochrome P450 family of enzymes referred to as ___

A

CYP enzymes

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13
Q

CYP are ___ proteins that require electrons and molecular oxygen (O2) to function

A

heme

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14
Q

where do the electrons come from

A

NADPH

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15
Q

What is the general formula for Phase 1 CYP

A

R + NADPH + O2 + H+ —CYP–> R-OH + NADP+ + H2O

*R = drug

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16
Q

CYP enzyme family is grouped by relatedness measured by ??

A

amino acid similarity

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17
Q

CYP 1 through 4 are known as ?

A

drug metabolizing enzymes

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18
Q

CYP 11, 17, 19, 21 are the ??

A

steroidogenic enzymes

*these also participate in drug metabolism of drugs that are steroid like in structure

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19
Q

first number refers to _____

A

family (having > 40% amino acid similarity)

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20
Q

letter refers to _____

A

subfamily (having > 59% amino acid similarity)

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21
Q

last number refers to ____

A

subtype of subfamily

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22
Q

CYP reactions:
aliphatic hydroxylation
(omega-1 hydroxylation)
(subterminal hydroxylation)

A
  • on “next to last” (penultimate) carbon on aliphatic chain
  • chain has to have 2 or more carbons

*carbon directly attached to an aromatic group more likely to be hydroxylated

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23
Q

aliphatic hydroxylation:

longer the chain = ?

A

higher the rate

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24
Q

CYP reactions:

aromatic hydroxylation

A

ED R groups tend to increase hydroxylation and favours para hydroxylation (where the OH and R are directly across from each other)

EW R groups tend to decrease hydroxylation

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25
In fused aromatic ring systems - usually only ___ ring will be hydroxylated
one
26
typically rings with _____ and __ groups will not be hydroxylated
halogens EW
27
``` CYP reactions: alkene oxidation (epoxidation) ```
epoxide is very reactive and may decompose non-enzymatically in H2O *alkene becomes an epoxide (three membered ring with O)
28
CYP reactions: | N or S oxidation
O is added to N or S
29
see slide 16 for: | N, O, or S dealkylation (v common)
ok man
30
CYP reactions: | deamination
see slide 16
31
What 3 ways can epoxides be hydrolyzed?
1) EH (epoxide hydrolase) or non-enzymatic 2) GST/ GSH (glutathione s transferase/ glutathione) 3) protein * See slide 17
32
describe the CYP enzyme active site
heme group attached to an active oxygen (very electron deficient and reactive) *oxygen is binded to the Fe2+ group and is converted into a reactive form
33
Substrate binding site generally prefers _____ substrates
hydrophobic | because we are trying to make it more hydrophilic
34
some drugs are CYP inhibitors and they have ____ groups on them that bind to the oxygen and inhibit the CYP enzymes
imidazole
35
??? are the most prominent example of CYP enzyme inhibitors
azole antifungals *they often also have large hydrophobic regions that bind to the CYP substrate binding pocket making them ideal CYP inhibitors
36
give 2 examples of azole antifungals
ketoconazole itraconazole *they are the most potent azole anti fungal inhibitors of CYP enzymes
37
_____ is also an inhibitor but less potent
fluconazole
38
Are esterases/amidases CYPs?
NO *but they do perform hydrolysis rxns and are Phase 1 enzymes
39
What are pro-drugs often designed as?
esters and amides - so then they can be hydrolyzed by esterases or amides to produce an active drug
40
What do Phase 2 enzymes require?
- substrate that is an unmodified drug or a drug modified by Phase 1 - require activated endogenous chemical (activated because it acts as a good leaving group for transfer of endogenous chemical to drug) - functional group on drug to modify
41
List the 6 types of Phase 2 conjugation
- glucuronide conjugation (most important) - glutathione conjugation - methylation - acetylation - sulfate conjugation - amino acid conjugation
42
Glucuronide conjugation: | enzyme?
UGT | UDP-glucuroosyltransferases
43
Glucuronide conjugation: | activated endogenous chemical?
UDP-GA | uridine diphosphate glucuronic acid
44
Glucuronide conjugation: | target functional groups?
OH ( most common) | SH, NH, COOH, R-NH-OH, R-S-OH
45
Glucuronide conjugation: | if product
excreted in urine
46
Glucuronide conjugation: | if product > 350 Da ?
excreted in feces
47
Glutathione conjugation: | enzyme?
GST | glutathione S transferase
48
Glutathione conjugation: | activated endogenous chemical?
GSH (yglutamyl-cystenyl-glycine) *this is not activated - therefore is an exception to the rule
49
Glutathione conjugation: | target functional groups?
any electrophile carbonyls substituted aromatic rings double bonds
50
Glutathione conjugation: | mostly excreted in ?
feces
51
Describe GST (glutathione S transferase)
- tripeptide found in all tissues - has a thiol group - toxic reactive metabolic intermediates of drugs are often detoxified by glutathione
52
Sulfate conjugation: | enzyme?
ST | sulfotransferase
53
Sulfate conjugation: | activated endogenous chemical?
PAPS | phosphoadenosine phosphosulfate
54
Sulfate conjugation: | target functional groups?
``` OH phenols catechols hydroxyl amines hydroxysteroids (estradiol) ```
55
Sulfate conjugation: | excreted in ?
urine
56
Methylation: | enzyme?
MTase | methytransferase
57
Methylation: | activated endogenous chemical?
SAM :) | S-adenosyl methionine
58
Methylation: | target functional groups?
O, N, S *this may reduce water solubility but it is more important biochemically to inactivate endogenous compounds
59
Methylation: | excretion ?
urine or feces
60
Acetylation: | enzyme?
AT (acetyl transferase) there can be NAT, OAT, or SAT NAT = most common
61
Acetylation: | activated endogenous chemical?
acetyl CoA | acetyl co enzyme A
62
Acetylation: | target functional groups?
mainly N sometimes O or S
63
Acetylation: | excreted in?
mostly urine
64
Amino acid conjugation: | enzyme?
AA-T (aminoacyl transferase) *most important in glycine
65
Amino acid conjugation: | activated endogenous chemical?
Drug-CoA *drug is activated usually through COOH
66
Amino acid conjugation: | target functional groups?
COOH
67
Amino acid conjugation: | mostly excreted in ?
urine

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