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PDA Block 1 > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

Importance of Drug Metabolism:

A
  1. Termination of drug action
  2. Drug activation
  3. Drug-drug interactions
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2
Q

Termination of drug action:

A
  1. For many drugs, the metabolites are more easily excreted from the body
    • Metabolites are most often more polar and hydrophilic
  2. For many drugs, metabolism inactivates the drug

Active drug ⇒ inactive metabolite

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3
Q

Drug activation:

A
  • Some drugs (prodrugs) are converted to their active form by metabolic enzymes

Prodrug (inactive) ⇒ active drug

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4
Q

Drug-drug interactions:

A
  • Many result from drug metabolism issues
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5
Q

What are some drugs that were withdrawn because of drug-drug interactions due to drug metabolism?

A
  • terfenadine
  • mibefradil
  • astemizole
  • cisapride
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6
Q

Phase I metabolism:

A
  • Oxidation, reduction, dealkylation, or hydrolysis reactions
    • often introduce or reveal a functional group
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7
Q

Phase II metabolism:

A

Conjugation of the drug or drug metabolite to an endogenous substrate molecule

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8
Q

How are drugs localized in the body?

A
  1. Organ distribution
  2. Subcellular distribution
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9
Q

Organ DIstribution:

A
  • Liver has the highest content overall of drug metabolizing enzymes
  • Other organs with significant content
    • gastrointestinal tract
    • kidneys
    • lungs
  • All tissues have some drug metabolizing enzymes
  • Distribution varies significantly for specific enzymes
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10
Q

Subcellular distribution:

A
  • Phase I enzymes: usually smooth ER (microsomal fraction)
  • Phase II enzymes: most are cytosolic
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11
Q

What is the first-pass effect?

A
  1. Applies to orally administered drugs
  2. Following absorption from the GI tract, the portal venous system transports them to the liver
    • Significant metabolism can occur prior to reaching the general circulation
  3. Drug metabolizing enzymes in the liver and/or intestine contribute to the first-pass effect
  4. Can greatly lower the oral bioavailability of a given drug
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12
Q

_______________ are hemeproteins that are major catalysts of _________ biotransformation reactions.

A
  • Cytochrome P450s
  • Phase I
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13
Q

Drugs with a _____________ need higher oral doses to match the effects or efficacy seen with IV administration

A

large first pass effect

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14
Q

What are two reasons for a low F (bioavailability)?

A
  1. Poor absorption
  2. Large first-pass effect
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15
Q

Name some drugs with a large first-pass effect:

A

Drug (F)

  • morphine (0.17 – 0.33)
  • meperidine (0.52)
  • aspirin (0.68)
  • propranolol (0.26)
  • labetalol (0.18 – 0.25)
  • metoprolol (0.38 – 0.50)
  • diltiazem (0.44)
  • verapamil (0.22)
  • nortriptyline (0.51)
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16
Q

Example: First-pass effect and oral dosing of morphine

If:

  • first-pass effect results in an oral F=0.33
  • an IV dose of 10 mg effectively relieves pain
A

Then:

  • an oral dose of 30 mg would be needed for same degree of pain relief
  • if the oral F=0.17, then an oral dose of 60 mg would be needed
    • Essentially, a patient will need 3-6x as much morphine than the IV dose
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17
Q

P450 Catalytic Cycle:

A
  1. Required components:
    • cytochrome P450
    • P450 reductase (flavoprotein)
    • NADPH
    • O2
    • drug (substrate)
  2. Monooxygenase-type reactions:
    • S + O2 + 2e– + 2H+ ⇒ SO + H2O
    • where S = substrate (drug)
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18
Q

Subcellular localization:

A
  • anchored to the cytoplasmic face of the smooth ER
  • one isoform of P450 reductase, but many cytochrome P450 isoforms
    • approx. 10–20 P450 molecules per P450 reductase
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19
Q

Human P450s:

A
  • 18 families
    • (CYP1, CYP2, CYP3)
  • 57 human P450 genes
    • (15 families largely involved)
  • Significant inter-individual variation
    • drug metabolism
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20
Q

How are drug metabolized by human P450s:

A
  1. Broad substrate specificity
    • each isoform can have several to hundreds of drug substrates
  2. Cytochrome P450 isoform contribution to human drug metabolism:

% of drugs handled by major isoforms:

  • CYP3A: 50%
  • CYP2D6: 25%
  • CYP2C9:15%
  • ≤5% each: CYP1A2, CYP2E1, CYP2A6, CYP2C19
  • ***DOES NOT equate to the amount of substrates each P450 can handle***
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21
Q

Other Phase I Enzymes
Flavin-containing monooxygenase (FMO):

A
  • Flavoprotein localized in smooth ER
  • Catalyze monooxygenation reactions, primarily of soft nucleophiles:
    • N, S, P & Se moeities
    • Cannot handle C (job of the P450s)
    • S + O2 + 2e– + 2H+ —> SO + H2O
    • Primarily N-oxidation and S-oxidation reactions
  • Hundreds of potential substrates:
    • some are P450 substrates, others are unique to FMOs
    • products are more polar and less toxic/active
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22
Q

Required components for FMOs:

A
  1. FMO
  2. NADPH
  3. O2
  4. drug (substrate)
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23
Q

FMO isoforms:

A

5 isoforms (FMO1-FMO5):

  1. FMO3
    • Liver, brain, kidney
    • 2–3% of hepatic protein (no other protein is this abundant)
  2. FMO1
    • Kidney, intestine
  3. FMO2
    • Lung (26% African-
      Americans)
    • Non-functional in
      Caucasians
  4. FMO4
    • Kidney, brain
  5. FMO5
    • Liver, kidney
24
Q

Examples of drug substrates
for FMO:

A
  • nicotine
  • cimetidine
  • ranitidine
  • spironolactone
  • imipramine
  • clozapine
  • olanzapine
25
Q

Dehydrogenases & Hydrolases:

A

Dehydrogenases

  1. Alcohol dehydrogenase (ADH)
  2. Aldehyde dehydrogenase (ALDH)

Hydrolases

  1. Epoxide hydrolase (EPHX)
  2. Carboxyl esterases
    • acetylcholine, procaine, cocaine, aspirin
  3. Amidases
    • lidocaine, peptide drugs
26
Q

Phase II Drug Metabolizing Enzymes:
Conjugative Reactions

A
  • conjugation of an endogenous chemical group to the drug
  • other examples:
    1. methylation
    2. glutathione conjugation
    3. glucoside conjugation
    4. amino acid conjugation
27
Q

What are the possible orders of phase I and phase II enzymes? What does this cooperativity depend on?

A
  • depends on drug, its functional groups, and available enzymes:
  1. drug → phase I → excretion
  2. drug → phase I → phase II → excretion
  3. drug → phase II → excretion
  4. drug → phase II → phase I → excretion
28
Q

Comparison of major classes of Phase II reactions:

Glucuronidation

A
  • High energy intermediate:
    • UDP-glucuronic acid
  • Functional groups needed on drug:
    • -OH, -COOH, -NH2, -NR2, -SH
  • Responsible Enzyme(s):
    • UDPglucuronosyl
      transferases (UGT)
  • Enzyme localization:
    • endoplasmic reticulum (lumenal face)
29
Q

Comparison of major classes of Phase II reactions:

Acetylation

A
  • High energy intermediate:
    • acetyl-CoA
  • Functional groups needed on drug:
    • -OH, -NH2
  • Responsible Enzyme(s):
    • N-acetyltransferases (NAT)
  • Enzyme localization:
    • cytosolic
30
Q

Comparison of major classes of Phase II reactions:

Sulfation

A
  • High energy intermediate:
    • Adenosine-3’- phosphate- 5’-phosphosulfate (PAPS)
  • Functional groups needed on drug:
    • -OH, -NH2
  • Responsible Enzyme(s):
    • sulfotransferases (SULT)
  • Enzyme localization:
    • cytosolic
31
Q

Comparison of major classes of Phase II reactions:

Glutathione conjugation

A
  • High energy intermediate:
    • drug itself: arene oxides, epoxides, etc.
  • Functional groups needed on drug:
    • aryl halide, arene oxide, epoxide, carbonium ion
  • Responsible Enzyme(s):
    • glutathione S-transferases (GST)
  • Enzyme localization:
    • cytosolic, some endoplasmic reticulum
32
Q

What is the net effect of most phase II reactions?

A
  • Metabolites are usually:
    • more polar (easier to excrete)
    • inactive or less toxic

Exceptions: acetyltransferases and methyltransferases

33
Q

% of drugs handled by phase II enzymes:

A

UGTs > STs > NATs, GSTs > TPMT

34
Q

What are some other properties of phase II enzymes?

A
  • Some are inducible
  • Most have many substrates
  • Vmax limited by conventional enzyme kinetics and conjugant supply
    • drug + conjugant → drug-conjugant complex
35
Q

Conjugation capacity & Abundance raw materials for cojugation:

Glucoronidation

A
  • Conjugation Capacity Abundance of Raw
    • High
  • Materials for Conjugation
    • High
36
Q

Conjugation capacity & Abundance raw materials for cojugation:

Acetylation

A
  • Conjugation Capacity Abundance of Raw
    • Variable
  • Materials for Conjugation
    • Variable
37
Q

Conjugation capacity & Abundance raw materials for cojugation:

Sulfation

A
  • Conjugation Capacity Abundance of Raw
    • Low
  • Materials for Conjugation
    • Low
38
Q

Conjugation capacity & Abundance raw materials for cojugation:

Glutathione conjugation

A
  • Conjugation Capacity Abundance of Raw
    • Low*
  • Materials for Conjugation
    • Low*
39
Q

Why is the conjugation capacity and abundance of GSH low in humans if the initial amount of GSH high?

A

It is not rapidly replenished

40
Q

What is enzyme induction?

A

Exposure to some drugs and environmental chemicals can markedly upregulate enzyme amount and/or activity

  • usually transcriptional increases:
    1. sometimes translational or protein stabilization
    2. more enzyme = faster metabolism
  • most cytochrome P450s (several isoforms) are inducible
    1. CYP2D6 not as inducible as others
  • some phase II enzymes (e.g. UGTs, GSTs) are inducible
    1. induced by environmental chemicals and some drugs
  • changes the overall proportion of drug-metabolizing enzymes
41
Q

Which P450 does ethanol induce?

A

CYP2E1

42
Q

Which P450 does tobacco smoke induce?

A

CYP1A

43
Q

What are the consequences of induction?

A

Can increase or decrease drug effects

  • Broad substrate specificity of many of these enzymes: a single inducer will simultaneously upregulate the ability to metabolize several drugs
    • will decrease effectiveness of drugs whose metabolites are inactive
    • will increase the effects/toxicity for drugs that are activated by the induced enzyme
  • Increase metabolism dramatically
  • Inducers are not quantitatively equal
44
Q

How long does induction take?

A

If transcriptional,

  • Maximal effects are seen in 1 – 2 days
45
Q

Is it possible for an inducer to be a substrate?

A

Inducers may or may not be substrates

46
Q

_________________ may inhibit the metabolism of several drugs.

A

Drug or environmental chemical

47
Q

Potential types of inhibition:

A
  • Competitive
    • competitive substrates are a major cause of drug-drug interactions
    • quinidine (CYP2D6)
    • furafylline (CYP1A2)
    • Many others
  • Bind CYP heme – disrupts catalytic activity (non-competitive)
    • cimetidine
    • ketoconazole, itraconazole
    • erythromycin
    • others
  • Suicide inhibitors (irreverisble—non-competitive)
    • ethinyl estradiol
    • levonorgestrol
    • secobarbital
48
Q

How long does inhibition take?

A

Immediate

49
Q

Extent of inhibition:

A
  • Highly variable:
    • Depends on enzyme and inhibitor
    • Small effects ⇒ very large effects
  • Several inhibitors of CYP2D6 can reduce activity to near zero:
    • amiodarone, bupropion, chloroquine, quinidine
    • diphenhydramine, fluoxetine, haloperidol, paroxetine
    • propoxyphene, terbinafine
50
Q

How does grapefruit juice interact with drugs?

A

Grapefruit juice increases drug absorption

  • Furanocoumarin is the responsible ingredient that inhibits intestinal CYP3A
  • Increasing the net amount of drug that reaches the general circulation
51
Q

How are FMOs affected by induction & inhibition?

A
  • Not significantly induced by clinically used drugs
  • Not significantly inhibited by clinically used drugs
    • less susceptible to competitive substrate inhibition than are P450s
  • Less potential for metabolic drug-drug interactions
52
Q

What are some other factors that influence drug
metabolism activity?

A
  • Age
    • Old and young
    • efficacy and/or toxicity
  • Genetics
  • Disease States
    • Hepatic diseases
    • Some cancers
    • Infections
      • cytokines decrease expression of some P450s
  • Gender
53
Q

Explain how gender is significant in regards to drug metabolism?

A
  • Clear differences in sex hormone metabolism
  • More recent findings:
    • Women require half the dose of zolpidem (Ambien®)
  • While CYP3A expression is overall similar between men and women, the clearance in women is actually slower
  • 6–7% of drugs have >40% pharmacokinetic differences between men and women
54
Q

What is the most common cause of acute hepatic failure?

A

Acetaminophen overdose

55
Q

What factors contribute to acetaminophen hepatotoxicity?

A

Interplay of:

  • multiple phase II reactions
  • phase I reaction
  • CYP2E1 induction

PDA Block 1 (13 decks)

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