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Drug Disposition > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

Why must metabolism be accounted for when determining dosage regimen?

A

Drug will be eliminated, so important to account for this to have therapeutic concentrations in the blood

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2
Q

Importance of drug metabolism in the body?

A

a dominant elimination route for many therapeutic drugs

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3
Q

Purpose of drug metabolism?

A
  • alters physchem properties of the molecule (easier elimination)
  • prevents drug accumulation
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4
Q

What is the most common cause of DDIs?

A

Inhibition of metabolic enzymes in the liver/intestine, which leads to reduced metabolism of drugs. severe DDIs lead to safety issues and even withdrawal from market

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5
Q

Characteristics of drug metabolising enzymes?

A
  • very broad substrate specificity
    (drugs, environmental chemicals, dietary chemicals, endogenous compounds)
  • predominantly located in the liver but also found in he intestine and kidney
  • ubiquitious - present in all animal species (original purpose was to protect from phytochemicals in diet). exposure is not more extensive via a wide range of drugs
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6
Q

What physicochemical changes can be made by metabolic enzymes to molecules?

A

Metabolites may be:

  • less lipophilic
  • more water soluble
  • pKa to stronger acids etc
  • better renally cleared

than the parent drug. purpose for much easier renal elimination

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7
Q

Pharmacological properties of metabolites?

A
  • metabolites usually don’t have a therapeutic effect (though there are a few exceptions, e.g. ezetimibe glucuronide)
  • metabolites aren’t generally toxic
  • sometimes plasma conc of metabolites can be greater than that of the parent drug
  • some metabolites inhibit metabolic enzymes/transporters - can contribute to DDIs
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8
Q

Role of the liver in drug metabolism/elimination?

A
  • most importnat due to size, blood flow and high enzyme levels
  • some drugs are eliminated unchanged via biliary excretion e.g. pravastatin
  • anatomical position - extensive first pass
  • infrastructure and subcellular localisation of enzymes
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9
Q

What are the phases of enzymes (+ examples) in the liver?

A
  • Phase 1 - CYP450 enzymes

- Phase 2 - e.g. UGT - glucuronidation

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10
Q

Where in the cells are most oxidation enzymes located?

A

Membrane bound so in the microsomes

- microsomes obtained through homogenisation and centrfugation

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11
Q

Uses of microsomes for in vitro studies?

A

Human microsomes from liver, intestine and kidney are widely used in drug development. can investigate metabolic possibility in those organs

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12
Q

Alternatives to microsomes for in vitro studies?

A

recombinant proteins (just one enzymes instead of all of them)
whole hepatocytes
chips

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13
Q

What are the different drug metabolism reactions - phase 1 and 2

A
  • oxidation
  • reduction
  • hydrolysis (phase 1 ^)
  • conjugation (phase 2)
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14
Q

Which of the drug metabolism reactions is the most significant?

A

oxidation

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15
Q

Which enzyme family catalyses oxidation reactions?

A

Cytochrome P450 - superfamily

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16
Q

What is the difference in metabolism mechanisms with many new drugs?

A

Immediately metabolised by conjugation (‘phase 2’)

17
Q

General principles of Phase 1 reactions

A

introduce or expose functional groups

18
Q

At which groups do oxidation reactions occur?

A

C, N or S

C - hydroxylations, aromatic or aliphatic
N and S oxidation
N- O- or S- dealkylation

19
Q

At which groups do reduction reactions occur?

A

Nitro or keto groups

20
Q

At which groups to hydrolysis reactions occur?

A

Amide or ester

21
Q

What are the three different types of oxidation reactions?

A

aromatic, aliphatic, de-alkylation

22
Q

What are the two mechanisms for oxidation reactions?

A

hydroxylation and cleavage

23
Q

What does aromatic oxidation result in?

A

Phenols

24
Q

What does aliphatic oxidation result in?

A

Alcohols

can occur on both the main chain and side chains

25
Q

What does O-dealkylation result in?

A

phenols/alcohols

26
Q

What does N-dealkylation result in?

A

Amines

27
Q

What other oxidative cleavage reactions are there?

A

deamination
desulphuration
dechlorination

28
Q

What does nitro group reduction result in?

A

Amines

29
Q

What contributes to nitro group reduction and what are the consequences of this?

A

Liver enzymes and gut flora

Gut flora can vary massively so leads to interpatient variability in metabolism

30
Q

What does Azo group reduction result in?

A

Amines

31
Q

What does keto group reduction result in?

A

Secondary alcohols

32
Q

What enzymes catalyse hydrolysis?

A

Carboxylesterases

33
Q

What can happen in sequential metabolism?

A
  • Phase 2 reactions (conjugation)
  • Further phase 1 reactions e.g. sequential oxidation on the same carbon (alcohol -> COOH)
    • or: sequential oxidation on a different e.g. hydroxylation of a demethylated metabolite
34
Q

What is parallel metabolism?

A

Competing metabolic reactions that occur to the parent molecule (not sequential, just different pathways the parent drug can go down)

35
Q

Points to use to predict the routes of drug metabolism

A

Any key functional groups - -OH, -NH2 or -COOH, may be susceptible to direct phase 2 metabolism (conjugation)

Other vulnerable groups - Esters, nitro, O-methyl etc

N or O present? Oxidative cleavage

Any other C groups vulnerable to oxidation (e.g. aromatic oxidation)

36
Q

Where in the molecule are reactions most likely to occur?

A

The alpha carbon - next to an electronegative moleucle e.g. O or N (or C=C)

  • N-C-R
  • O-C-R
  • C=C-C=R

also consider side chain hydroxylations and aromatic hydroxylations

37
Q

What in vivo methods can be used to identify metabolites and start building up metabolic pathways for drugs in development?

A
  • Products in excreted urine (mainly terminal metabolites)

- Products circulating in plasma

38
Q

What in vitro methods can be used to identify metabolites and start building up metabolic pathways for drugs in development?

A
  • Products formed in incubations with liver tissue (e.g. liver microsomes)
39
Q

Why is complete recovery of metabolites difficult?

A

Some metabolites are unstable or non-recoverable

Drug Disposition (11 decks)

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