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IMED2002 UWA > Pharmacokinetics 3: Drug metabolism > Flashcards

Pharmacokinetics 3: Drug metabolism Flashcards

1
Q

What is drug metabolism characterised by?

A

Chemical structure modified by Drug-Metabolising Enzymes (DMEs)

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2
Q

What does drug metabolism usually do to drugs?

A

It usually makes lipophilic drugs more hydrophilic.

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3
Q

Why are drugs made more hydrophilic when being metabolised?

A

To make them better substrates for efflux transporters.

To make them more blood and urine soluble for excretion.

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4
Q

Where are drug metabolism enzymes located?

A

Mostly in the liver but also in:

Gut wall

Kidneys

Lungs

Skin

Brain

Testes

Heart

Gut microbiome

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5
Q

What are the 2 possible fates for drugs?

A

In general, hydrophilic drugs undergo minimal metabolism in the liver and are excreted in urine.

Lipophilic drugs are either converted into hydrophilic compounds and excreted in urine or they are excreted in bile.

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6
Q

What are the main classes of drug metabolism?

A

Oxidative metabolism (Oxygenation, hydroxylation, N-dealkylation)

Conjugative metabolism (Sulfonation acetylation, glucuronidation)

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7
Q

What happens as a result of oxidative metabolism?

A

A new functional group is added or exposed.

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8
Q

What happens as a result of conjugative reactions?

A

New chemical bonds are formed between drugs and endogenous molecules using the new functional groups. The added endogenous molecules are often very hydrophilic.

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9
Q

What does metabolism do to half life of drugs?

A

It decreases their half life (time needed for plasma concentration to fall by 50%).

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10
Q

What is the usual consequence of drug metabolism?

A

A reduction in biological activity (metabolite may not fit into the drug receptor)

However, in some cases they can retain biological activity. (prodrugs use this function)

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11
Q

What is a prodrug?

A

A drug that is inactive unless metabolised

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12
Q

What is cytochrome P450 (CYP)?

A

A family of drug metabolising enzymes with wide specificity for drugs. (only a handful are important for human drug metabolism)

Cytochrome P450s metabolise about 75% of all drugs

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13
Q

How large are cytochrome P450 enzymes?

A

Approximately 50 kDa mass

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14
Q

What metal is contained in cytochrome P450?

A

They are iron containing haemproteins

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15
Q

What functional group is located in active site of cytochrome P450?

A

Protoporphyrin IX located at base.

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16
Q

How do cytochrome P450 enzymes carry out their action?

A

Size and shape of active site varies between CYP family members.

Amino acids on surface of active site provide binding options for drugs and orient drug towards the haem group.

O2 binding and redox changes in Fe atom during catalytic cycle results in formation of Fe^5=O species.

Fe^5=O donates O atom to oxidation-prone site in drug.

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17
Q

What kind of enzyme is cytochrome P450?

A

A monooxygenase (it provides metabolite with 1 oxygen)

18
Q

What does NADPH-CYP reductase do?

A

It provides the electrons necessary for metabolism of drugs by cytochrome P450

19
Q

Where does the NADPH and CYP reactions take place in hepatocytes?

A

Within the smooth endoplasmic reticulum. Lipophilic drugs diffuse into CYP active site via lipid bilayer

20
Q

What is first pass metabolism?

A

CYP expression is strong in the gut wall and liver.

Metabolism of drugs can occur before they reach systemic circulation.

21
Q

Which enzyme is especially common in gut wall?

A

CYP3A4/7

22
Q

What does first pass metabolism result in?

A

Lower bioavailability in orally administered drugs.

23
Q

How can first pass metabolism be bypassed?

A

Using parenteral routes of administration of drugs

24
Q

What factors is the influx transporter important for?

A

Drug metabolism and distribution

25
Q

What are the essential roles for transporters in metabolism?

A

Hepatocellular uptake which ensures a good substrate supply to CYPs.

Efflux of metabolites via bile

Efflux of metabolites to blood for eventual removal by urine.

Efflux transporters also return metabolites to the blood for excretion via urine.

26
Q

Example of transporter influence on drug metabolism:

A

Sumatripan is used to treat migraines. When OCT1 is not present there is no liver uptake of sumatripan which resulted in 214% higher plasma AUC for sumatripan.

27
Q

Which CYP enzymes are commonly involved in metabolism of drugs?

A

CYP3A4 (preferred substrate diazepam)

CYP2D6 (preferred substrate codeine)

CYO2C9 (preferred substrate Ibuprofen)

28
Q

What kind of interactions (DDIs) are CYPs involved in that are clinically important?

A

They can be induced by some chemicals and inhibited by others.

Since relatively few CYPs metabolise most drugs, there is a high probability of interactions

29
Q

What are pharmacogenetic issues of CYP?

A

Individual responses to drugs can be influenced by genetic variations in CYP.

30
Q

What causes inhibition of drug metabolism?

A

2 drugs competing for same CYP isoform. (Clinical effects on the inhibited drug take 3 - 4 days to appear)

31
Q

What are the 2 mechanisms of metabolism inhibition?

A

Competitive inhibition (most common and reversible)

Mechanism-based inhibition: Less common and irreversible. (Inhibition caused by chemically unstable metabolite and attacks CYP enzyme to inactivate protein)

32
Q

What clinical problems arise from inhibition of drug metabolism?

A

Exaggerated drug effect due to impaired clearance. (can result in toxicity)

Diminished drug effect due to impaired metabolic activation of prodrug

33
Q

DDI example:

A

SSRI antidepressants and codeine.

Fluoxetine inhibits CYP2D6 blocking formation of morphine + morphine-6-G (analgesic) from codeine. This problem can be avoided with newer SSRIs that don’t block 2D6.

34
Q

When are CYP inhibitors used?

A

When it is desired for metabolism to slow down for a drug. (eg, using cobicistat [P450 inhibitor] for HIV anti-retroviral medication)

35
Q

What kinds of drugs and chemicals increase CYP expression?

A

Smoking, alcohol, etc.

36
Q

How does drug metabolism get induced?

A

Usually via a drug receptor (xenosensors) after binding there is release from cytosol and xenosensors act as transcription factors at CYP gene promotors.

37
Q

How long does induction take to be seen clinically?

A

~1 week

38
Q

Can drugs induce their own metabolism?

A

Yes, example is carbamezapine

39
Q

How do xenosensors induce metabolism?

A

They bind to drug and to XRE (xenobiotic response element) which promote transcription of genes coding for CYP enzymes.

40
Q

What are the clinical problems that arise from induction of CYP receptors?

A

Poor drug effect due to accelerated hepatic clearance

41
Q

What are the clinical implications of CYP2D6 polymorphisms?

A

Therapeutic window can vary between patients

IMED2002 UWA (29 decks)

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