Aromatic hydroxylation

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Aromatic hydroxylation
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Aliphatic hydroxylation
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Epoxidation
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Dealkylation
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CYP1A

• Metabolize polycyclic hydrocarbons
• Are induced by polycyclic hydrocarbons
• Found in cigarette smoke
• Associated with cancer
• CYP1A1
• is inducible
• extrahepatic
• CYP1A2
• is constitutively expressed only in liver
• Is inducible

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CYP1A

• Polymorphisms (primarily CYP1A1)
• Expression polymorphism
• Structural gene polymorphism
• In vivo assay (CYP1A2)
• Caffeine metabolism

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CYP 2A

• CYP2A6 and CYP2A13
• CYP2A6 is polymorphic
• Responsible for nicotine metabolism

CYP 2B

• CYP2B6
• CYP2B1 and CYP2B2 are major forms in rats
• was originally thought to be a minor form in
  humans

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CYP2C

• CYP2C8, CYP2C9, CYP2C18, and CYP2C19 are major
  forms in humans
• Hormonally regulated in rodents (growth hormone)
• Metabolize about 30 of commonly used drugs
• Omeprazole
• Diazepam
• In vivo substrates
• S-mephenytoin (CYP2C19)
• Flurbiprofen (CYP2C9)

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CYP2D6

• Metabolize many important drugs
• Codeine
• Dextromethorphan
• Polymorphisms
• Mutation in the structural gene
• Related to increased cancer risk (rapid
  metabolizers)
• In vivo substrate
• Debrisoquine
• Dextromethorphan

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CYP2E1

• Is uncoupled
• Produces superoxide and hydrogen peroxide
• Forms reactive intermediates
• Nitrosamine carcinogens
• acetaminophen

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CYP2E1

• Is uncoupled
• Forms reactive intermediates
• Associated with acetaminophen toxicity
• Ethanol inducible
• Polymorphisms
• Linked to cancer
• Role in alcohol-related liver dysfunction
• In vivo substrate
• chlorzoxazone

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CYP3A4/5

• Major P450 in humans - metabolizes over 50 of
  commonly used drugs
• Is inducible by numerous drugs
• CYP3A4 not polymorphic but wide variation in
  activity (due to CYP3A5)
• In vivo substrates (hepatic and intestinal)
• Erythromycin
• Alfentanil

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Hydrolysis reactions

• Plasma, liver, kidney, and all tissues
• Esterase
• Succinylcholine apnea
• Amidase
• Epoxide hydrolase
• Found in liver and all tissues
• Both microsomal and soluble forms
• Inducible by phenobarbital and 3-methylcholanthren
  e

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Hydrolysis reactions

• Esterase (plasma, liver, and kidney)
• Succinylcholine apnea
• Amidase (liver)
• Epoxide hydrolase
• Found in liver and all tissues
• Both microsomal and soluble forms
• Inducible by phenobarbital and 3-methylcholanthren
  e

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Hydrolysis reactions

• Esterase (plasma, liver, and kidney)
• Succinylcholine apnea
• Amidase (liver)
• Epoxide hydrolase
• Found in liver and all tissues
• Both microsomal and soluble forms
• Inducible by phenobarbital and 3-methylcholanthren
  e

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Conjugations reactions(phase 2)

• Glucuronidation
• Sulfate conjugation
• Acetylation
• Glutathione conjugation
• Methylation
• Glycine conjugation

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Acetylation
N-acetyl transferase
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Glutathione conjugation
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Methylation

• Methytransferases
• Cytoplasm and endoplasmic reticulum
• S-adenosymethionine

Amino acid conjugation

• Usually as glycine conjugates
• Mitochonria and cytoplasm

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One Compartment Model

• Intravascular Bolus

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One Compartment Model

• Extravascular

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Two Compartment Model

• Intravascular Bolus

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Two Compartment Model

• Extravascular

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Apparent Volume of Distribution
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Continuous IV Infusion
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Multiple IV Administration
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Multiple Extravascular Administration
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