1-43 Drug Metabolism II

Question 1

Acetominophen: drug metabolism

Answer 1

• “phase 1” unnecessary because OH group “pre-lubbed” on acetominophen
  
  • low dose: phase 2 either GLUCURONIDATION or SULFATION, either way nontoxic intermediate in excreted in urine
  • high dose: phase 1ish CYP2E1 and CP3A4 add hydroxyl group anyways, molecule unhappy and rearragnes to form NAPQI (evil electrophile, toxic intermediate)
    
    • luckily: glutathione can bind NAPQI and saves cell from destruction
    • unluckily: if glutathione depleted and cannot save, NAPQI binds to nucleophillic cell macromolecules in liver cells and causes liver cell death
      
      • ​sadly: glutathione does not cross cell membranes well so we cannot use as antiodote
      • happily: N-acetylcysteine (NAC) conjugates directly with NAPQI and can replace glutathione stores, also antiooxidant properties

Question 2

Polymorphisms in CYP dependent oxidations (ALL)

Answer 2

• CYP3A4: bell shaped curve in population, theremore not known to contirbute significanlty to individual variability
• CYP2D6: most common polymorphisms
  
  • Poor metabolizers: inheritance of 2 mutant CYP2D6 alleles
    
    • 9% caucasions
    • 2% AA
    • 5% hispanic
    • Asian <1%
  • Rapid metabolizers: duplication or amplyfication of CYP2D6 genes, excessibe expression of enzyme high metabolic capacity
    
    • North Africans: 30%​
  • Many drugs used to treat CNS disorders use CYP2D6!
    
    • Ex: metoprolol: B1s blocker to treat elevated heart rate/HTN/arrhythmia poor metabolzier require lower dose, rapid metabolizer require higher dose
    • Ex: codeine (weak agonist): converted by CYP2D6 to morhpine (full agonist), rapid metabolizers have adverse effects to codeine because rapidly converted to morphine causing sedation / respiratory depression therefore use lower doses in rapid meta, do not use in poor metabolizers
• CYP2C19: 15-25% asians poor metabolizers
  
  • Diazepam: long-acting benzodiazepine, requires CYP2C19 to funcitonalize the molecule via N-dealkylation then via hydrozylation for the glucuronideation inactivation necessary for excretion
    
    • half life of diazepam can be >4x longer than normal
  • Omeprazole: proton pump inhibiors, tx excessive acid secretion (ulcers), irreversibly blocks pp
    
    • therefore reduce doses for poor metabolizers population
• CYP2C9: 10-35% caucasians poor metabolizers
  
  • Warfarin: increases clotting time (anticoag) to prevent stroke, blocks carboxylation of coagulation factors, side effect increased bleeding, TI=1
    
    • changes number od days required for stable anticoagulation because slowly metabolizing
  • Ibuprofen (NSAID): pain relief antiinflam, inhbits both housekeeping (COX-1) (maintains normal kidney and GI fxn with prostaglnadin synthesis)and painful (COX-2) cyclooxygenases (makes the painful prostaglandins)
  • Celecoxib (NSAID): pain relief antiinflam, used to treat post op pain, selectively inhibits the cyclooxygenase (COX-2) responsible for pain
    
    • ​poor metabolizers require lower doses

Question 3

Polymorphisms in CYP dependent oxidations (CYP3A4)

Answer 3

• CYP3A4: bell shaped curve in population, theremore not known to contirbute significanlty to individual variability

Question 4

Polymorphisms in CYP dependent oxidations (CYP2D6)

Answer 4

• CYP2D6: most common polymorphisms
  
  • Poor metabolizers: inheritance of 2 mutant CYP2D6 alleles
    
    • 9% caucasions
    • 2% AA
    • 5% hispanic
    • Asian <1%
  • Rapid metabolizers: duplication or amplyfication of CYP2D6 genes, excessibe expression of enzyme high metabolic capacity
    
    • North Africans: 30%​
  • Many drugs used to treat CNS disorders use CYP2D6!
    
    • Ex: metoprolol: B1s blocker to treat elevated heart rate/HTN/arrhythmia poor metabolzier require lower dose, rapid metabolizer require higher dose
    • Ex: codeine (weak agonist): converted by CYP2D6 to morhpine (full agonist), rapid metabolizers have adverse effects to codeine because rapidly converted to morphine causing sedation / respiratory depression therefore use lower doses in rapid meta, do not use in poor metabolizers

Question 5

Polymorphisms in CYP dependent oxidations (CYP2C19)

Answer 5

• CYP2C19: 15-25% asians poor metabolizers
  
  • Diazepam: long-acting benzodiazepine, requires CYP2C19 to funcitonalize the molecule via N-dealkylation then via hydrozylation for the glucuronideation inactivation necessary for excretion
    
    • half life of diazepam can be >4x longer than normal
  • Omeprazole: proton pump inhibiors, tx excessive acid secretion (ulcers), irreversibly blocks pp
    
    • therefore reduce doses for poor metabolizers population
  • Clopidogrel: antiplatelet agent, prodrug, active metabolite requires activation by CYP2C19
    
    • therefore poor metabolizers are not properly anticoagulated post surgery and have higher risk for stroke post stenting

Question 6

Polymorphisms in CYP dependent oxidations (CYP2C9)

Answer 6

• CYP2C9: 10-35% caucasians poor metabolizers
  
  • Warfarin: increases clotting time (anticoag) to prevent stroke, blocks carboxylation of coagulation factors, side effect increased bleeding, TI=1
    
    • changes number od days required for stable anticoagulation because slowly metabolizing
  • Ibuprofen (NSAID): pain relief antiinflam, inhbits both housekeeping (COX-1) (maintains normal kidney and GI fxn with prostaglnadin synthesis)and painful (COX-2) cyclooxygenases (makes the painful prostaglandins)
  • Celecoxib (NSAID): pain relief antiinflam, used to treat post op pain, selectively inhibits the cyclooxygenase (COX-2) responsible for pain
    
    • ​poor metabolizers require lower doses

Question 7

Polymorphism in CYP independent OXIDATIONs- alcohol metabolism

Answer 7

Ethanol via ALCOHOL DEHYDROGENASE -> Acetaldehyde via ALDEHYDE DEHYDROGENASE -> Acetate

• build up of acetaldehyde causes unpleasant alchol symptoms

1. Alcohol dehydrogenase reaction is enhanced: accumulation of acetaldehyde and second step of rxn cannot keep up, 90% chinese population 5-20% caucasians
2. Aldehyde dehydrogenase is deficient: accumulation of acetaldehyde in 30-50% of Chinese/Japanses

Question 8

Polymorphisms in Hydrolysis

Answer 8

• Plasma cholinesterase responsible for the degredation of succinylcholine is variable
• if the amount of activity is reduced then could over-intibate a patient requiring ventilation and NM paralysis

Question 9

Genetic variations in N-acetyltransferase (NAT)

Answer 9

• biomodal distribution, fast and slow
• slow acetylators: have LESS NAT (not due to abnormal enzyme)
  
  • phenotype: 50% blacks/whites, associated with higher incidence of drug induced bladder cancers, toxic effects of isoniazid and other NAT substrates
    
    • Isoniazid (antimicrobial): toxic effects of high doses because cannot inactivate quickly

Question 10

Genetic variations in Glutathione (phase II metabolism rxns)

Answer 10

• GST and glutathion-null genotypes
  
  • increased risk of cancers, CML
  • Mu genotype: 50% caucasians, absence of GST activity linked to leukemia, lung, colon, bladder cancers
  • Theta genotype: 60% chinese koreans: absence of GST activity linked to increased risk of leukemia and prostate cancers
    
    • toxicity of cancer chemotherapy drugs because they cannot be cleared by glutathione conjugation

Question 11

Why the broad substrate spectrum of CYP3A4?

Answer 11

1. Large active site, can accomidate many diff drugs
2. shapes dont matter for CYP3A4

Question 12

CYP1A2

Answer 12

• metabolizes methyl xanthines
  
  • caffeine
  • theophylline

Question 13

CYP2E1

Answer 13

• toxicity producing in acetaminophen metabolism, makes NAPQI
• may be induced by ethanol or isoniazid
  
  • low doses of ethanol use the dehydrogenases for metabolism
  • higher doses use and INDUCE CYP2E1

Question 14

Ethanol and acetaminophen toxicity

Answer 14

1. Ethanol induces CYP2E1 to create toxic intermediate NAPQI
2. Ethanol reduces glutathione conentration and prevents it from rescuing NAPQI

Question 15

Pollutants that can affect CYPs

Answer 15

• CYP1A: induced by environmental pollutants (smoking, factories, also by charcoal foods and cruciferous vegetables)
• Benzoapyrines: worse cultrit to produce cancers from enviornemnt pollutants
  
  • found in coal tar, cig smoke, charbroiled foods

CYP1A induction causes benzoapyrines to form epoxides

• benxoapyrene traverses PM and binds AHR (aryhydrocarbon receptor, ligand activated TF), AHR traverses to nucleus and initiates CYP1A gene transcription

Question 16

Herbal remedies that can affect CYPs

Answer 16

1. Ginkgo: enhance memory, induces CYP2C19 and CYP2C9 and CYP3A4
2. Echinacea: enhance immune system, inhibits CYP1A2 but induces CYP3A4
3. St. John’s Wort: treat mild/mod depression, induces CYP3A4, 2C9, 2C19, 2E1 hence enhances metabolism or oral contraceptives via CYP3A4 induction
   
   • get pregnant whilst on birth control AHH
   • goes straight to nucleus and binds PXR on a response element on DNA, coactivation and such and increases CYP3A4 gene transcription->protein up

Question 17

what if two-coadministered substrate drugs use the same CYP?

Answer 17

• if residual levels of one drug remains at the active site, then it may inhibit the metabolism of the other drug
  
  • ex: omeprazole binds so tightly that it will inhibit the CYP2C19 for other drugs that would need to use it