Lecture 8 Flashcards

Biotransformation/Metabolism I

1
Q

Drug Metabolism

A
  • Major factor in drug excretion and plasma levels
  • Drug inactivation or activation can be connected to it (parent drug being inactivated or activated)
  • Mixed actions can also occur from multiple metabolites forming with different activities
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2
Q

Where does metabolism occur?

A
  • Wherever metabolic enzymes are present
  • Mainly liver
  • Also lungs, skin, kidneys, and brain
  • Almost every tissue has some metabolic capacity
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3
Q

Phase I

A

-Usually produces a more polar metabolites by introducing or unmasking a functional group
-Excreted if metabolites are sufficiently polar
-Many undergo subsequent reactions
EX: Cytochrome P450 (inserts oxygen), hydrolases (hydrolysis of esters and amides), reductases (nitro, keto, azo)

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4
Q

Key Enzymes (4)

A
  1. NADPH-cytochrome P450 reductase - flavoproteins
  2. Cytochrome P450 - heme proteins
  3. Flavoprotein Monooxygenases - similar reactions as P450 (N-/S- oxidations mainly)
  4. Hydrolytic Reactions - cytosolic enzymes in liver, kidney, and plasma that are esterases and amidases
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5
Q

Phase II

A
  • Conjugate Reactions
  • Conjugates usually are inactive, but can lead to drug activation or toxic metabolites
  • Typically drugs metabolize by two or more Phase II enzymes
  • Requires co-factors that can be depleted
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6
Q

Metabolism Exceptions

A

-Sometimes Phase I is AFTER Phase II
-Some drugs have functional groups that form a conjugate directly
EX: Isoniazid

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7
Q

Acetaminophen

A
  • 5% of acetaminophen that is metabolized by CYP450 is an highly reactive electrophile
  • Fast, reactive (toxic) intermediates being formed depends on the amount of glutathione available
  • More toxic species are present when patient is an alcoholic
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8
Q

Phase I Oxygenases (3)

A
  1. Cytochrome P450 - C and O oxidation, dealkyation, others
  2. Flavin-containing Monooxygenases - N-, S-, and P- oxidation
  3. Epoxide Hydrolases - Hydrolysis of epoxides
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9
Q

Phase II Transferases (5)

A
  1. Sulfotransferases - transfer of sulfate
  2. UGT - transfer of glucuronic acid
  3. GST - transfer of glutathione
  4. NAT - transfer of acetyl group
  5. Methyltransferases - transfer of methyl group
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10
Q

Other Enzymes (3)

A
  1. Alcohol dehydrogenases - reduction of alcohols
  2. Aldehyde dehydrogenases - reduction of aldehydes
  3. NQO - reduction of quinones
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