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Pharm Block 1 > 5 - Drug Metabolism > Flashcards

5 - Drug Metabolism Flashcards

1
Q

What processes prevent continuous drug action?

A

Elimination/excretion

Metabolism

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2
Q

What is the importance of drug metabolism?

A

For many drugs, the metabolites are more easily excreted from the body because they’re usuaully more polar of hydrophilic than the parent drug.

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3
Q

In many causes, metabolism ______ the drug, but in some causes metabolism converts ______ into an active state.

A

Inactivates

Can also convert inactive prodrugs to their active form.

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4
Q

What is a common cause of drug-drug interactions?

A

Metabolism issues.

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5
Q

If someone is taking 2 drugs, what is the risk for significant adverse event relating to drug-drug interactions? What about if they’re taking 7 drugs?

A

2: 13% risk
7: 82% risk

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6
Q

What the the main function of phase I enzymes? What actions do they carry out?

A

Introduce of reveal a functional group via oxidation, reduction, dealkylation, or hydrolysis.

Usually adding an oxygen atom

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7
Q

What the the main function of phase II enzymes? What actions do they carry out?

A

Conjugation of a drug or drug metabolite to an endogenous substrate molecule.

Drug + conjugant -> drug-conjugant

Often adds a large polar conjugant.

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8
Q

Where are drug metabolizing enzymes localized? Which has the highest amount of these enzymes?

A

Portals of entry and exit from the body:

  • Liver (highest overall)
  • GI tract
  • Kidneys
  • Lungs

All tissues have some, and the type os enzymes varies by location.

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9
Q

What is the subcellular distribution of Phase I and II enzymes?

A

I: usually smooth endoplasmic reticulum (SER)

II: most are cytosolic

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10
Q

What is the first pass effect for orally administered drugs? What are the two types of first pass effect?

A

Following absorption from the GI tract, portal venous system transports drugs to the liver where significant metabolism occurs prior to reaching the general circulation.

Hepatic and intestinal.

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11
Q

What does the first affect have a large impact on?

A

Bioavailability, and thus higher oral doses may be necessary for desired effects to occur.

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12
Q

What are two reasons for low F ( bioavailability)?

A

Poor absorption

Large first pass effect

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13
Q

What are the two major types of phase I enzymes?

A

Cytochrome P450’s (CYPs)

Flavin-Containing Monooxygenases

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14
Q

What do P450 enzymes need? What is the result of their action?

A

They have a heme group and need a drug substrane, a source of electrons (NADPH), an accessory protein called P450 reductase, and molecular oxygen.

Result: add one atom of O onto a drug.

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15
Q

What are some types of P450-mediated reactions?

A

Dealkylation, aromatic hydroxylation, aliphalic hydroxylation, oxidation, and deamination.

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16
Q

What is the subcellular location of P450 enzymes? What about P450 reductase? What is the ratio.

A

Single isoform of P450 in all cell types.

Many different isoforms of CYP450 in cell that are anchored to the outer face of the ER.

Ratio is 10-20 P450s per P450 reductases.

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17
Q

What is the nomenclature of P450 enzymes?

A

CYP means cytochrome P450

first number is the genes family (needs 40% similarity in aa sequence to identify with a fam)

next letter is the gene subfamily (needs >55% identitiy)

last number (if any) is the isoform

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18
Q

How many P450 families exist in humans? How many of their genes are involved in drug metabolism? What can alter their catalytic activity?

A

3 families: CYP1, CYP2, CYP3

15 human genes invovled in drug metabolism within the 3 families.

Individual differences in isoforms can result in large differences in drug metabolism.

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19
Q

Which P450 metabolizes more than 1/2 of all drugs?

A

CYP3A

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20
Q

Which three P450 isoforms handle 90% of all metabolizable drugs?

A

CYP3A
CYP2D6
CYP2C9

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21
Q

Does the relative CYP isoform content equate to the significance of role in drug metabolism? Support your answer.

A

NO.

CYP2D6 is only 1.5% of the liver expression but metabolizes 50% of drugs

CYP1A2 is 13% of the liver’s expression but only handles 5% of drugs.

22
Q

What is required for reactions with Flavin-containing monooxygenases (FMO)? What are the benefits this this? What are the products like?

A

Substrates need to have a soft nucleophile (N, S, P, or Se)
-this excludes non-substrates rather than selecting for substrates.

Even broader substrate profile: drugs, dietary compounds, xenobiotics.

Products are usually more polar and less toxic.

23
Q

Other than a substrate with a soft nucleophile, what do FMOs need? What is the net effect?

A

NADPH as an e donor.
O2, one of which will be added to the drug and the other will leave as water.

Net effect: adding oxygen, but in a different way than P450s.

*FMO can’t out Oxygen on anything like P450s can.

24
Q

What isoform of FMO is the biggest player in drug metabolism? Where is it found? How much hepatic protein does it make up?

A

FMO3

Found in the LIVER, brain, and kidney.

Most abundant protein in the liver (2-3%)

25
Q

What type of reactions do Phase II enzymes carry out? What is their action?

A

Glucuronidation, sulfation, acetylation, and glutathione conjugation.

Conjugate drugs.

26
Q

Is there an order in which drugs interact with phase I and II enzymes before excretion?

A

NO; nothing that holds true at all times, it varies.

Some drugs interact with only one, some interact with both before excretion.

27
Q

How are Phase II enzymes named? Where are they located?

A

The name of the conjugate followed by transferase.

All phase II enzymes are located in the cytosol, except UDP-glucuronosyl transferase (UGT) is located in the ER.

28
Q

What enzymes is responsible for glucuronidation? Acetylation?
Sulfation?
Glutathione conjugation?

A

UDP-glucuronosyl trnasferase (UGT)

N-acetyltransferase (NAT)

Sulfotransferase (SULT)

Glutatione S-transferase (GST)

29
Q

What is the net effect of phase II enzymes?

A

Generally makes things a lot more polar (exception is N-acetyltransferases) and make metabolites less active than the parent drug.

30
Q

What is a significantly important compound that is metabolized by UGTs?

A

Bilirubin.

Babies don’t have a lot of UGT (UDP-glucuronosyl transferase) yet which is why they accumulate bilirubin and become jaundiced.

31
Q

What is Vmax effected by for phase II enzymes?

A

The finite supply of conjugant molecules and the amount of the enzyme.

There’s a direct relationship between high amount of conjugant and conjugation capacity.

32
Q

Describe the conjugation capacity and the abundance of raw materials for junguation for each:

  1. Glucuronidation
  2. Sulfation
  3. Glutatione conjugation
  4. Acetylation
A
  1. High conjucation capacity, high abundance of raw materials for conjugation
  2. Low capacity, low amount of materials
  3. Low, low (hard to replace once used)
  4. Variable, variable
33
Q

What are the two most common types of drug metabolism interactions?

A

Enzyme induction and enzyme inhibition.

34
Q

What is enzyme induction?

A

Exposure to drugs and environmental chemicals that markedly up-regulates drug metabolizing enzyme amount and/or activity.

Usually through transcriptional increases
(more enzyme = faster metabolism)

35
Q

What CYP is not as inducible as other P450 enzymes? Which is the most potent inducer?

A

2E1 is less inducible (induced by ethanol).

CYP3A is the most potent inducer that can accelerate the metabolism of 50% of all drugs.

36
Q

What are some unique aspects of CYP2D6?

A

Not very abundant - 1.5% of total P450 content but handles 25% of all drugs through competitive inhibition.

Not very inducible compared to other CYPs.

Very susceptible to competitive inhibition.

37
Q

What increases drug metabolism?

A

Enzyme induction.

This can affect many drugs handled by that enzyme.

38
Q

Induction can _____ or _____ drug effects. What does this depend on?

A

Increase or decrease

This depends on whether metabolite is active or inactive.

Induction will activate inactive drugs and inactivate active drugs.

39
Q

How long does induction take? How long does it take to return to non-induced levels when the inducer is withdrawn?

A

Maximal effects can occur in 1-2 days or longer if repetitively exposed to small amounts of inducer.

Depends on turnover of induced enzyme - days to weeks.

40
Q

Are all substrates inducers? Are all inducers substrates?

A

Inducers of specific isoforms may or may not be substrates.

41
Q

What effect does inhibitors of drug metabolizing enzymes have?

A

Usually decrease their activity NOT gene expression

42
Q

What are three types of P450 inhibitors?

A
  1. Competitive substrates: major cause of CYP-related drug interactions
  2. Non-competitive: bind non-substrate site to disrupt conformation/activity; some bind heme group.
  3. Irreversible inhibitors: can only be fixed by making more enzyme
43
Q

How long does inhibition take?

A

Immediate because it’s usually due to interaction with the enzyme itself.

44
Q

How much does inhibition affect drug metabolism? What can some inhibitors of CYP2D6 do?

A

Highly variable - depends on enzyme and inhibitor.

Reduce activity to near zero - potential for 0 order kinetics making it appear that the person doesn’t have any of that enzyme activity.

45
Q

What is one notible CYP inhibitor?

A

Grapefruit juice! : increases absorption of drugs inactivated by CYP3A by inhibiting intestinal CYP3A and thereby increasing the net amt of drug that reaches circulation.

Remember CYP3A handles 50% of drugs.

46
Q

Can FMOs be inducted and/or inhibited? Why?

A

Not significantly induced or inhibited because there’s already so many made by the liver so you can’t/don’t need more.

You also don’t need inhibition because you have so much FMO that you wouldn’t be able to out-compete it.

*Drugs handled by FMO have less potential for metabolic drug-drug interactions.

47
Q

What are other factors that influence drug metabolism activity?

A

Age, genetics, disease states, and gender.

48
Q

What did recent studies find out about drug metabolism and its relation to gender? What drug was this discovered with?

A

That women require half the dose of zolpidem (ambien) than men despire having similar CYP3A expression.

Women clear the drug slower.

6-7% of drugs have >40% pharmacokinetic differences between men and women.

49
Q

Why do neonates metabolize drugs slower than adults?

A

Neonates have longer drug T1/2 because they are markedly deficient in adult drug metabolizing enzyme isoforms.

50
Q

Why is acetaminophen the most common cause of acute hepatic failure in the US?

A

BEcause it’s present in over 100 over-the-counter products and people don’t realize they’re taking too much because it’s called APAP and pts don’t recognize that as the name for acetaminophen.

51
Q

How is acetaminophen metabolized? Name the three ways. What induced the dangerous path?

A
  1. 15-17% by SULT to inactivate (can be saturated)
  2. 80% by UGT to inactivate it (hard to saturate)
  3. CYP2E1 turns APAP into NAPIQ, which causes hepatic necrosis if not converted by GSH (can be used up quickly).

CYP2E1 is induced by ethanol.

52
Q

What is Tadalafil (Cialis) predominantly metabolized by?

A

CYP3A via methylation and glucuronidation to become inactivated.

This means that drugs that inhibit CYP3A can increase tadafil exposure.

Also means that drugs that induce CYP3A can decrease tadafil exposure.

Pharm Block 1 (11 decks)

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