phase 1

• Drug metabolism


  The metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems
• Xenobiotic metabolism


  A form of drug metabolism
• Drug metabolism


  Often converts lipophilic chemical compounds into more readily excreted polar products
• Drug metabolism


  Its rate is an important determinant of the duration and intensity of the pharmacological action of drugs
• Drug metabolism


  Can result in toxication or detoxication - the activation or deactivation of the chemical
• The major metabolites of most drugs are detoxication products
• Drugs are almost all xenobiotics
• Other commonly used organic chemicals are also xenobiotics, and are metabolized by the same enzymes as drugs
• This provides the opportunity for drug-drug and drug-chemical interactions or reactions
• Phase I reactions


  • Oxidation
  • Reduction
  • Hydrolysis
  • Cyclization
  • Decyclization
• Oxidation


  Involves the enzymatic addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver
• Oxidative reactions


  Typically involve a cytochrome P450 haemoprotein, NADPH and oxygen
• Classes of pharmaceutical drugs that utilize oxidation for metabolism

  • Phenothiazines
  • Paracetamol
  • Steroids
• If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point
• Many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate combines with the newly incorporated functional group to form a highly polar conjugate
• Oxidation enzymes


  • Cytochrome P450 (CYP families)
  • Flavin containing monooxygenase (FMO)
  • Monoamine Oxidase (MAO)
  • Aldehyde Oxidase and Xanthine Dehydrogenase
  • Peroxidases
  • Alcohol Dehydrogenases (ADH)
  • Aldehyde Dehydrogenases (ALDH)
• Cytochrome P450 (CYP)


  Mixed-function oxidation, with substrates including phenothiazines, paracetamol, and steroids
• Flavin containing monooxygenase (FMO)


  Single-protein mixed-function oxidase, with a more restricted range of substrates (generally soft nucleophiles, almost always N, S, and P atoms)
• Monoamine Oxidase (MAO)


  Oxidizes amines, particularly biogenic amines involved as neurotransmitters
• Aldehyde Oxidase and Xanthine Dehydrogenase

  Oxidize substrates with a different stoichiometry and mechanism than P450 and FMO, with the source of the oxygen atom being H2O instead of O2
• Peroxidases


  Involve high valent FeO chemistry, with reactions including radical propagation, dimer formation, dealkylation, oxygenation, and the formation of reactive halides
• Alcohol Dehydrogenases (ADH)


  Catalyze the reversible oxidation of alcohols to aldehydes
• Aldehyde Dehydrogenases (ALDH)


  Catalyze the oxidation of aldehydes to carboxylic acids, which is usually not reversible
• Reduction enzymes


  • NADPH-P450 Reductase
  • Quinone Reductase (NQO)
• NADPH-P450 Reductase


  Transfers electrons from NADPH to P450, and can also reduce oxidized molecules in a second-order reaction
• Quinone Reductase (NQO)


  Catalyzes the reduction of quinones to hydroquinones, avoiding the generation of radicals
• Hydrolysis enzymes


  • Epoxide Hydrolase
  • Esterases and Amidases
• Epoxide Hydrolase


  Catalyzes the addition of H2O to epoxides, using an acyl intermediate mechanism
• Esterases and Amidases


  A large and heterogeneous family of enzymes that collectively constitute the third largest group of reactions on drugs, behind P450s and UGTs