Lec 66: Drug Absorption and Distribution and Drug Metabolism I Flashcards

1
Q

Identify the major metabolic pathways by which drugs are chemically modified.

A
  • Phase I or Non-synthetic (drug is split)
  • Phase II or Synthetic (something is added to the drug to make it more hydrophilic via conjugation)
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2
Q

Define the Phase I metabolic reaction.

A

Phase I metabolic reactions: HOR - Hydrolysis, Oxidation, Reduction Usually convert the parent drug to a polar metabolite by introducing or unmasking a functional group (-OH, NH2, SH)

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3
Q

Define the Phase II metabolic reaction.

A

Phase II metabolic reactions: *GAS* = Glucuronidation, Acetylation, Sulfation - Point is to increase polarity

  • Conjugation with a polar or charged group
  • require a donor molecule as source of conjugated group
  • High capacity reactions (not rate limiting)
  • Usually follow a non-synthetic (Phase I) reaction
  • Facilitate excretion and usually inactivate
  • Biological function
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4
Q

Name the major cytochrome P450 substrates for CYP1A2:

A

Substrates: Acetaminophen (important because of toxicity factor), Caffeine, Theophylline, Warfarin

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5
Q

Name the major cytochrome P450 substrates for CYP2A6:

A

Substrates: Warfarin (minor), Zidovudine

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6
Q

Name the major cytochrome P450 substrates for CYP2C9:

A

**S-Warfarin (CYP2C9 is the main enzyme that metabolizes the biologically active form of warafin)

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7
Q

Name the major cytochrome P450 substrates for CYP2C19:

A

Substrates: Diazepam, Omeprazole, Propanolol

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8
Q

Name the major cytochrome P450 substrates for CYP2D6

A

Substrates: Amitriptyline, Codeine (converts to morphine), Fluoxetine, Hydrocodone, Timolol

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9
Q

Name the major cytochrome P450 substrates for CYP2E1

A

Substrates: Acetaminophen, Ethanol

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10
Q

Name the major cytochrome P450 substrates for CYP3A4

A

*the really important one*

Substrates:

  • steroids (testosterone, progesterone, cortisol, etc.)
  • calcium channel blockers (nifedipine, diltiazem, verapamil)
  • benzodiazepines (diazepam, triazolam)
  • amiodarone
  • **erythromycin (and other macrolide antibiotics)
    • Can lead to toxicity if administered when CYP3A4 is blocked
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11
Q

Explain the critical steps in the P450 reaction pathway, including the roles of NADPH, cytochrome P450 reductase and molecular oxygen.

A

Net reaction is oxidation R-H -> R-OH

Requires:

  • NADPH important Cofactor - used 2x
  • molecular Oxygen
  • Cytochrome P450 reductase
  1. Drug substrate (R-H) combines with oxidized (Fe3+) cytochrome P450 to form a binary complex.
  2. NADPH donates an electron to the flavoprotein, NADPH cytochrome P450 reductase, which in turn reduces the oxidized CYP450-drug complex.
  3. The same flavone reductase introduces a second electron (also from NADPH) to reduce molecular oxygen and form an “activated oxygen” - CYP450-drug complex.
  4. This complex transfers oxygen to the drug substrate to form the oxidized drug product (R-OH), liberates water, and leaves free oxidized (Fe3+) CYP450 to react with another drug molecule.
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12
Q

Identify other non-P450 Phase I reactions.

A
  • Oxidation–Flavin monooxygenases, alcohol dehydrogenase, amine oxidases
  • Hydrolysis–Particularly esterases and amidases
  • Reduction–Nitro- and Azo- compound reduction by reductases
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13
Q

List the major conjugation reactions (Phase II).

A
  • Glucuronidation (the major conjugation reaction)
  • Sulfation
  • Acetylation
  • Glutathione conjugation
  • Glycine conjugation
  • Methylation
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14
Q

Explain mechanisms that result in increased (enzyme induction) or decreased (enzyme inhibition) rates of drug metabolism or altered distribution (through changes in drug transporter expression).

A
  • Mechanism of enzyme induction: Ligand (substrate of metabolism enzyme) binds nuclear receptors which activate transcription of metabolic enzymes (CYP450 -> metabolize drugs; Conjugating enzymes; drug transporters). the metabolic enzyme then acts on the ligand or potentially other drugs in the body.
  • Effect is increased metabolism of drugs:
    • increased toxicity from metabolites
    • Ineffective treatments due to drug being metabolized too fast
  • Mechanism of enzyme inhibition: drugs that bind, modify, or compete for the substrates (like NADPH for P450 enzymes) of active metabolic enzymes.
    • ex: erethormycin covalently binds to the heme group of P450 enzymes => inactivation
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15
Q

Recognize the factors (drugs, over-the-counter or herbal medications, dietary factors) that may influence drug metabolism in humans.

A

Nutrition:

  • Grapefruit and grapefruit juice: a component of the juice binds to and inactivates CYP3A4
  • Isosafrole, safrole: CYP1A1, CYP1A2 inhibitor - found in root beer and perfume.
  • Ethanol: CYP2E1 inducer (note importance in acetaminophen metabolism)
  • Charcoal broiling: CYP1A enzyme induction
  • Tobacco (not really a food): CYP1A induction (benzo[a]pyrene)
  • Cruciferous vegetables (like broccoli): CYP1A induction

Drug Classes Known to Cause Clinically Relevant Interactions:

  • Anti-epileptics (low therapeutic index, CYP metabolism)
  • Protease inhibitors (co-administration with CYP inducers, example: rifampin)
  • Statins (metabolized by CYP3A enzymes in gut and liver)
  • Warfarin (metabolized by CYPs; highly protein bound)
  • Digoxin (multiple interactions, low therapeutic index)
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16
Q

Describe the mechanism of some common drug-drug interactions.

A
  • Alteration in elimination - reducing ability for an organ to clear a drug leads to increased drug in body
  • Physico-chemical interactions (divalent cations and fluroquinolones)
  • Additive/synergistic functional interactions - the stacking effects of drugs
    • stacking antibiotics -> increase thearopy
    • stacking antidepresents -> increase toxisity
    • stacking blood thinners -> increase bleeding
17
Q
A