NADPH- Cyt. P450 reductase P450 S SOH O 2 H 2 O e NADPH NADP +

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    13-Jan-2016

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  • Aromatic hydroxylation

  • Aliphatic hydroxylation

  • Epoxidation

  • Dealkylation

  • CYP1A Metabolize polycyclic hydrocarbons Are induced by polycyclic hydrocarbonsFound in cigarette smokeAssociated with cancerCYP1A1 is inducibleextrahepaticCYP1A2 is constitutively expressed only in liverIs inducible

  • CYP1APolymorphisms (primarily CYP1A1)Expression polymorphismStructural gene polymorphismIn vivo assay (CYP1A2)Caffeine metabolism

  • CYP 2ACYP2A6 and CYP2A13CYP2A6 is polymorphicResponsible for nicotine metabolism

    CYP 2BCYP2B6 CYP2B1 and CYP2B2 are major forms in ratswas originally thought to be a minor form in humans

  • CYP2CCYP2C8, CYP2C9, CYP2C18, and CYP2C19 are major forms in humansHormonally regulated in rodents (growth hormone)Metabolize about 30% of commonly used drugsOmeprazoleDiazepamIn vivo substratesS-mephenytoin (CYP2C19)Flurbiprofen (CYP2C9)

  • CYP2D6Metabolize many important drugsCodeineDextromethorphanPolymorphismsMutation in the structural geneRelated to increased cancer risk (rapid metabolizers)In vivo substrateDebrisoquineDextromethorphan

  • CYP2E1Is uncoupledProduces superoxide and hydrogen peroxideForms reactive intermediatesNitrosamine carcinogensacetaminophen

  • CYP2E1Is uncoupled Forms reactive intermediatesAssociated with acetaminophen toxicityEthanol induciblePolymorphisms Linked to cancer Role in alcohol-related liver dysfunctionIn vivo substratechlorzoxazone

  • CYP3A4/5Major P450 in humans - metabolizes over 50% of commonly used drugsIs inducible by numerous drugsCYP3A4 not polymorphic but wide variation in activity (due to CYP3A5)In vivo substrates (hepatic and intestinal)ErythromycinAlfentanil

  • Hydrolysis reactionsPlasma, liver, kidney, and all tissuesEsteraseSuccinylcholine apneaAmidaseEpoxide hydrolaseFound in liver and all tissuesBoth microsomal and soluble formsInducible by phenobarbital and 3-methylcholanthrene

  • Hydrolysis reactionsEsterase (plasma, liver, and kidney)Succinylcholine apneaAmidase (liver)Epoxide hydrolaseFound in liver and all tissuesBoth microsomal and soluble formsInducible by phenobarbital and 3-methylcholanthrene

  • Hydrolysis reactionsEsterase (plasma, liver, and kidney)Succinylcholine apneaAmidase (liver)Epoxide hydrolaseFound in liver and all tissuesBoth microsomal and soluble formsInducible by phenobarbital and 3-methylcholanthrene

  • Conjugations reactions(phase 2)GlucuronidationSulfate conjugationAcetylationGlutathione conjugationMethylationGlycine conjugation

  • AcetylationN-acetyl transferase

  • Glutathione conjugation

  • MethylationMethytransferasesCytoplasm and endoplasmic reticulumS-adenosymethionineAmino acid conjugationUsually as glycine conjugatesMitochonria and cytoplasm

  • One Compartment ModelIntravascular Bolus

  • One Compartment ModelExtravascular

  • Two Compartment ModelIntravascular Bolus

  • Two Compartment ModelExtravascular

  • Apparent Volume of Distribution

  • Continuous IV Infusion

  • Multiple IV Administration

  • Multiple Extravascular Administration