chap2

• Phase I of drug metabolism involves functionalization reactions, including oxidative, reductive, and hydrolytic biotransformations
• The purpose of Phase I is to introduce functional polar groups (e.g., OH, COOH, NH2, SH) into the xenobiotic molecule to produce a more water-soluble compound
• Oxidation in drug metabolism involves the Mixed Function Oxidase System, with Cytochrome P450 being responsible for transferring an oxygen atom to the substrate
• Examples of Cytochrome P450 enzymes include CYP3A4, the most dominant isoform in the liver, and CYP2D6, which is involved in metabolizing antidepressants
• Cytochrome P450 enzymes nomenclature:

  • CYP: Cytochrome P450 enzymes
  • Arabic Number: Family (CYP1, CYP2)
  • Capital Letter: Subfamily (CYP1A, CYP2C, CYP3A)
  • Arabic Number: Individual enzyme in a subfamily (CYP1A2, CYP2C9)
• Oxidation of alcohols in drug metabolism:

  • Primary alcohol → Aldehyde → Carboxylic Acid
  • Secondary alcohol → Ketone
• Reduction plays a role in metabolizing compounds containing carbonyl, nitro, and azo groups, converting carbonyl compounds to alcohol derivatives and nitro/azo compounds to amino derivatives
• Example of reduction in drug metabolism: Reduction of aldehydes and ketones to alcohols, e.g., Chloral Hydrate to Trichloroethanol
• Hydrolysis in drug metabolism is important for drugs containing the ester/amide functionality
• Phase II of drug metabolism involves conjugation reactions to attach small, polar, and ionizable endogenous compounds to form water-soluble conjugated products
• Conjugated metabolites are readily excreted in urine and generally lack pharmacological activity and toxicity in humans
• Examples of conjugation reactions in drug metabolism:

  • Methylation and Acetylation to terminate or attenuate biological activity
  • Glutathione (GSH) Conjugation to protect against chemically reactive compounds
• Examples of conjugation reactions in drug metabolism:

  • Methylation and Acetylation to terminate or attenuate biological activity
  • Glutathione (GSH) Conjugation to protect against chemically reactive compounds
• Glucuronidation is the most common conjugation reaction in drug metabolism, involving enzymes like Glucuronyl transferase and metabolizing substances like Morphine, Paracetamol, and Chloramphenicol
• Sulfate conjugation, well-developed in infants, is exemplified by drugs like Paracetamol
• Glycine & Glutamine conjugation is used to conjugate carboxylic acids, converting substances like Benzoic acid to hippuric acid
• Glutathione or Mercapturic Acid Conjugation is an important pathway for detoxifying chemically reactive compounds, with Glutathione (GSH) acting as a free radical scavenger
• Acetylation in drug metabolism involves the acetyl group supplied by acetyl CoA, important for drugs containing primary amino groups like Hydralazine, Isoniazid, and Sulfonamides
• Methylation in drug metabolism leads to the inactivation of biogenic amines, producing pharmacologically inactive metabolites
• Sites of drug biotransformation include the liver, the most important organ for drug metabolism and detoxification, and the intestinal mucosa, especially significant for orally administered drugs
• The First-Pass Effect occurs when orally administered drugs pass through the liver before reaching the bloodstream, potentially decreasing oral bioavailability
• Drugs metabolized extensively by the First-Pass Effect include Isoproterenol, Lidocaine, Morphine, Nitroglycerin, and others
• Enzyme induction can be caused by substances like Phenytoin, Phenobarbital, and Chronic Alcoholism, while enzyme inhibitors include Metronidazole, Erythromycin, and others