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Pharm > Drug metabolism > Flashcards

Drug metabolism Flashcards

1
Q

Outline the requirements for CYP mediated oxidation reaction (phase I)

A

Drug
Cofactor for reduction (NADPH/NADH)
Molecular oxygen
Protons

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2
Q

What are the products of a CYP ocidation reaction

A

Oxifised drug
NADP+
H2O

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3
Q

What is the common structure of cytochrome enzymes

A

Porphyrin ring with iron in the middle CATALYTIC

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4
Q

Explain how the cyt p450 causes oxidation of a drug

A

Drug binds at the site of the porphyrin ring containing catalytic iron. Interacts with Fe3+

NADPH or NADH provides an electron. That electron is picked up by iron at the active site. Fe3+–> Fe2+

Oxygen added, which binds at the active site (near the iron and the drug). The electron that the iron gained from the NADPH is now transferred to the oxygen. Iron converts back Fe2+–>Fe3+

Electron makes oxygen aggitated

Another electron is then picked by the iron. Fe3+–>Fe2+

Another electronic rearrangement. Fe3+–>F2+ again. Second electron picked up by the molecular oxygen which is now very unstable

One of the O molecules from molecular oxygen reacts with 2 protons to become water. The other O molecule reacts with the drug to form the hydroxyl group

Substrate released

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5
Q

T/F for the oxidation of the drug with Cyt p450, only 1 NADPH was needed

A

F…. 2 were needed. 1 molecular oxygen needed

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6
Q

Which molcules can be used as reducing agents in cytp450 reactions

A

NADPH or NADH (sometimes)

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7
Q

T/F cytp450 involves hydroxylation

A

T! It is an oxidation reaction BUT
Oxidation reactions generally start with a hydroxylation step
catalysed by the P450 system.

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8
Q

Which step in CYTP450 oxidation is rate limiting

A

The second reduction

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9
Q

T/f all compounds are oxidised in the same position with CYTP450

A

f…..

in aliphatic compounds e.g. pentobarbitone (a barbiturate), OH group added in any of the carbons

there is a main metabolite (pictured)

-OH added.

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10
Q

What is acetanilide

A

It is an aromatic structure

Oxidised by CYTP40

When oxidised forms paracetemol

(-OH added)

but this is not sold as a pro-drug because it is toxic for blood cells

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11
Q

What is N-demethylation

A

Oxidation of carbon ATTACHED to nitrogen (this tertiary nitrogen acts as substrate for the cytp450)

Oxidised N-methyl group.

Formaldehyde drops off (HCHO), and a proton gained.

e.g. Imipramine (tertiary nitrogen) –>desimipramine

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12
Q

What is O-demethylation

A

Oxidise carbons attached to oxygen.

Formaldehyde again drops off (HCHO)

e.g. CODEINE TO MORPHINE (in this reaction, happens very well insome people and no tin others due to differing CYTP450)

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13
Q

What is N-oxidation

A

This is oxidation of the nitrogen group on a teritary nitrogen with lone pair of electrons (trimethylamine)

Lone pair of electron on the nitrogen- it donates it to an oxygen

Makes amine oxide (oxide of tertiary amines)

NOT BY CYTP450 by flavine containing monooxygenase

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14
Q

What occurs in people with low flavine contianing monooxygenase

A

This is a polymoprhic enzymes so differing amounts

In N-oxidation, the substrate is a tertiary nitrogen with lone pair of electrons.

Smells like fish

Flavine containing mono-oxygenase allows donation of the lone pair of electrons to an oxygen

In people with low levels, the teritiary nitrogen with lone pair accumulates (the trimethylamine), and they smell bad.

FISH ODOUR SYNDROME

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15
Q

Is there a cure for fish odour syndrome

A

No

Have to avoid trimethylamine

But it’s everywhere including when eating meat in choline which is converted to trimethylamine

High rates of suicide etc.

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16
Q

Outline oxidation of ethanol

A

Ethanol –> acetaldehyde by alcohol dehydrogenase

Acetaldehyde –> acetic acid by aldehyde dehydrogenase

NOT CYTP450

REVERSIBLE

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17
Q

Differentiate ethanol metabolism to most other metabolism

A

Alcohol dehydrogenase is zero order kinetics.,

Most other enzymes (CYTP450, flavine containing monopoxygenase) are 1st order

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18
Q

T/F CYTP450 is not a reductase

A

Mostly true, but can act as a reductase very rarely in some circumstances

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19
Q

Where do reductase reactions occur (phase 1)

A

GI tract by bacterial reductases

e.g. prontosil –> sulphanilamide

prontosil is an antibacteria drug, but of a non antibiotic type. Can’t be used against gut bacteria

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20
Q

T/F oxidation and reduction happen in equal meausre

A

F… reduction far less common than oxdation

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21
Q

When does hydrolysis of a drug occur

What enzymes

What are the products

A

On esters or amides

e.g. procainamide

ESTERASES and AMIDASES

Products include COOH and amino groups

22
Q

T/F xenobiotic metabolism only happens in the liver

A

F

23
Q

Phase 1 metabolism can introduce functional groups such as what

A

–OH, -NH2, -SH or –COOH.

act as handles for phase II metabolism

24
Q

T/F most of the products of phase I are biologically inactive

A

T

25
Q

What is the effect of phase I on drug polarity

A

Have little effect on drug polarity.

26
Q

Phase II metabolism involves which reactons and which enzyme

A

Glucuronidation
(Glucuronyl transferase)

Methylation
(methyl transferase)

Sulphation
(Sulphotransferase)

Glutathione
(Glutathione-S-transferase)

Aminoacid conjugation
(Acyl transferase)

Acetylation
(Acetyl transferase)

27
Q

What is the aim of phase II metabolis

A

To put big large endogenous polar molecules onto the drug

28
Q

Differentiate acetyl transferase and acy transferase

A

Acetyl transferase involved in acetylation (phase II metabolism)

Acyl transferase involved in amino acid conjugation in phase II metabolism

29
Q

What is the product of phase II reactions like

A

Conjugate is almost always pharmacologically inactive

Less lipid soluble

Easier to excrete

30
Q

What is the most common phase II reaction

A

Glucoronidation

31
Q

What is required for phase II metabolism

A

Enzyme (i.e. the transferase)
+
Conjugating agent

32
Q

Why does phase II require energy

A

To make the conjugating agents

33
Q

List the conjugating agent for each of the phase II reactions

A

Glucuronidation- UDP-glucuronic acid (UDPGA)

Acetylation- acetyl CoA

AA conjugation- Glycine, glutamine, taurine

Methylation- S-adenosyl-methionine

Sulfation- 3’-phosphoadenosine-5’-phosphosulphate

Glutathione conjugation- glutathione

34
Q

Which AA are most likely to be used in phase II metabolism

A

Glycine, glutamine, taurine

35
Q

What are the target functional groups for each of the phase II

A

Glutathione: ELECTROPHILES

Acetylation: -OH, -NH2

AA conjugation: -COOH

Methylation: -OH, -NH2

Sulfation: -OH, -NH2

Glucoronidation: -OH, -COOH, -NH2, -SH

36
Q

T/f sulfation conjugates -SH groups

A

F…. the target group of sulphation is -NH2 and -OH

-SH groups are targeted by glucoronidation

37
Q

Why is glutathione important

A

Because electrophiles, which they target, are going to destroy DNA as this is the most electrophilic biomaterial

38
Q

Explain the metabolism of ibuprofen

A

Phase I- OH group added by CYTP450

Phase II- GLUCURONIDATION

UDGPA added with glucucornyl transferase)

39
Q

Where is the glucuronide group added in Glucuronidation

A

Glucuronic acid part transferred to

an electron rich atom (N, O or S)

40
Q

Where are glucuroindes excreted

A

Often in the bile

41
Q

Outline acetylation reactions

A

Amine group, oxygen or sulphur group which was exposed in phase I

Acetyl CoA added

Producted is an acetylated amine

CoA generated

42
Q

Give an example of acetylation reaction

A

Sulphanamide

acetyl CoA acts as a donor molecule. Donates acetyl group. Forms acetylated amide

43
Q

Outline methylation

A

Target is N, O or S

S-adenosyl methionine acts as donor compound

donates methyl group

44
Q

Why does methylation occur, even though phase II is meant ot make compounds more waer csoluble and easier to excrete.

Methylation clearly makes it harder to excrete as more lipophiic

Give example

A

It is a reactionthat occurs endogenously

E.g. NA–> A

The body mistakenly converts drugs with a similar strucutte to adrenalines (e.g. AMPHETAMINE)

45
Q

Why is sulfation really good

wHAT’S THE PROBLEM

A

It works opposite to methylation and makes a really polar product

PAPS takes a lot of energy to make (this is the conjugating agent)

But it can make really lipophilic compounds really water soluble

46
Q

Outline the sulfation

A

Sulfotransferases catalyse transfer of sulphate (conjugating agent is 3’-phosphoadenosine-5’-phosphosulphate
) to substrates

e.g. -OH, -NH2 are the targets

47
Q

Give an example of sulfation

A

Paracetemol. Hydroxyl group on the paracetmol has sulfate group donated by PAPS.

PAP is produced as well as the sulfated derivative

48
Q

T/F when grinding paracetmol, it would usually dissolve in water

A

F. Normally very lipopholic

When you give PAPS with it, it will have sulfate donated and become really water soluble and dissolve

49
Q

Outline conjugaton with glutathione

A

E.g. halogen or electrophile is the targeted

e.g. benzyl chloride (not drug). glutathione. Thiol groups attacks molecule to form the thiol derivative WITH HCL

50
Q

What type of molecule is glutathione

A

Tripeptide

glycine, glutamine and cysteine

51
Q

What is glutathione used for

A

Protective factor for removal of toxic compounds for DNA

52
Q

Which organs have high levels of glutathione

When are levels not high enough

A

Kidneys and liver

E.g in paracetmol overdose, this system is overwhelmed (NAPQI, an electrophile and derivative of phase I metabolim, needs to be glucoronidated)

Pharm (33 decks)

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