Lec 66: Drug Absorption and Distribution and Drug Metabolism I

Question 1

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

Answer 1

• 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)

Question 2

Define the Phase I metabolic reaction.

Answer 2

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)

Question 3

Define the Phase II metabolic reaction.

Answer 3

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

Question 4

Name the major cytochrome P450 substrates for CYP1A2:

Answer 4

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

Question 5

Name the major cytochrome P450 substrates for CYP2A6:

Answer 5

Substrates: Warfarin (minor), Zidovudine

Question 6

Name the major cytochrome P450 substrates for CYP2C9:

Answer 6

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

Question 7

Name the major cytochrome P450 substrates for CYP2C19:

Answer 7

Substrates: Diazepam, Omeprazole, Propanolol

Question 8

Name the major cytochrome P450 substrates for CYP2D6

Answer 8

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

Question 9

Name the major cytochrome P450 substrates for CYP2E1

Answer 9

Substrates: Acetaminophen, Ethanol

Question 10

Name the major cytochrome P450 substrates for CYP3A4

Answer 10

*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

Question 11

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

Answer 11

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.

Question 12

Identify other non-P450 Phase I reactions.

Answer 12

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

Question 13

List the major conjugation reactions (Phase II).

Answer 13

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

Question 14

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).

Answer 14

• 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

Question 15

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

Answer 15

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)

Question 16

Describe the mechanism of some common drug-drug interactions.

Answer 16

• 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