Pmoc semie lesson 8

• Phase 2 drug metabolism


  Also known as the conjugation phase, involves the chemical modification of drugs or their metabolites (from Phase 1 metabolism) by attaching (conjugating) them with an endogenous substance
• Phase 2 metabolism


  • Usually results in the formation of a more water-soluble compound, facilitating its excretion from the body through urine or feces
  • Unlike Phase 1 reactions, which may introduce a functional group to the molecule, Phase 2 reactions generally involve the linkage of large polar groups to the drug or its metabolites
  • The primary goal is to increase the molecular weight and polarity of the substances, making them less active pharmacologically and easier to eliminate
• Types of Conjugation Reactions

  • Glucuronidation
  • Sulfation
  • Methylation
  • Acetylation
  • Conjugation with Amino Acids
• Glucuronidation


  Most common Phase 2 reaction, mediated by UDP-glucuronosyltransferase (UGT) enzymes, involves the addition of glucuronic acid to drugs, increasing water solubility

  
• Sulfation


  Catalyzed by sulfotransferase (SULT) enzymes, involves the addition of sulfate groups to phenols, alcohols, and amines, enhancing their solubility and excretion
• Methylation


  Mediated by methyltransferases, involves the addition of methyl groups to oxygen, nitrogen, or sulfur atoms in drugs, alters the activity of the drug and facilitates its excretion
• Acetylation


  Catalyzed by N-acetyltransferases (NATs), involves the transfer of acetyl groups to amines, aids in solubility and excretion
• Conjugation with Amino Acids


  Typically involves glycine or glutamine, mediated by various enzymes depending on the substrate and amino acid, further increases solubility
• Types of Enzymes Involved in Phase 2 Metabolism

  • UDP-Glucuronosyltransferases (UGTs)
  • Sulfotransferases (SULTs)
  • N-Acetyltransferases (NATs)
  • Glutathione S-transferases (GSTs)
  • Methyltransferases
  • Amino Acid Conjugating Enzymes
• UDP-Glucuronosyltransferases (UGTs)


  Catalyze the conjugation of glucuronic acid to drugs, making them more water-soluble

  
• Sulfotransferases (SULTs)


  Transfer a sulfo group (SO3) from the donor molecule 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to drugs or metabolites, enhancing their water solubility
• 1. Acetyltransferases (NATs)


  Acetylate drugs or their metabolites, a reaction that can either increase or decrease water solubility depending on the compound

  
• Glutathione S-transferases (GSTs)


  Catalyze the conjugation of the antioxidant glutathione to reactive metabolites, crucial for detoxifying electrophilic compounds
• Methyltransferases


  Transfer methyl groups from S-adenosylmethionine (SAM) to drugs or their metabolites, affecting the activity and solubility of the compounds
• Amino Acid Conjugating Enzymes


  Catalyze the conjugation of amino acids, such as glycine or glutamine, to drugs or their metabolites, enhancing their excretion
• The activities of these Phase 2 enzymes can vary greatly among individuals due to genetic polymorphisms, leading to differences in drug metabolism rates and responses
• Understanding these variations is important for optimizing drug therapy and minimizing adverse drug reactions
• Common Drugs that Undergo Significant Phase 2 Metabolism

  • Acetaminophen (Paracetamol)
  • Ibuprofen
  • Aspirin (Acetylsalicylic Acid)
  • Morphine
  • Lorazepam
  • Azathioprine
  • Tamoxifen
  • Isoniazid
  • Bilirubin
  • Propofol

  
• Acetaminophen (Paracetamol)


  Primarily undergoes glucuronidation and sulfation, a small portion is also metabolized via the glutathione conjugation pathway

  
• Ibuprofen


  Undergoes glucuronidation, a nonsteroidal anti-inflammatory drug (NSAID) conjugated with glucuronic acid to be excreted in the urine
• Aspirin (Acetylsalicylic Acid)


  Metabolized through both Phase 1 and Phase 2 pathways, with Phase 2 involving glucuronidation of salicylic acid, the main metabolite of aspirin

  
• Morphine


  Undergoes glucuronidation to form morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active), which are then excreted in the urine

  
• Lorazepam


  One of the benzodiazepines that undergoes significant glucuronidation, directly conjugated without undergoing Phase 1 metabolism, leading to its inactivation and excretion

  
• Azathioprine


  Metabolized in part through methylation by thiopurine methyltransferase (TPMT), the activity of TPMT varies among individuals, affecting the drug's efficacy and toxicity

  
• Tamoxifen


  A prodrug that undergoes Phase 1 metabolism to active metabolites, which are then subject to sulfation and glucuronidation

  
• Isoniazid


  Acetylated by N-acetyltransferase 2 (NAT2), the rate of acetylation varies among individuals, categorized into slow and fast acetylators, which affects the drug's toxicity and efficacy

  
• Bilirubin


  Conjugation of bilirubin with glucuronic acid allows its excretion in bile, and variations in this process can lead to jaundice
• Propofol


  Undergoes glucuronidation, rapidly metabolized through conjugation, contributing to its short duration of action
• Propofol, nicknamed the "milk shot" or the "milk of amnesia", is a medication that is injected into the body to decrease levels of consciousness and increase a lack of memory, making it a commonly used drug for general anesthesia and sedation
• Propofol works very quickly; it only takes about 30 seconds for it to take effect once it is injected into the vein, and the recovery time is fast
• Factors Affecting Phase 2 Metabolism

  • Genetic Variability
  • Age
  • Liver Function
  • Nutrition
• Genetic Variability


  Genetic polymorphisms in the genes encoding Phase 2 enzymes can lead to significant interindividual differences in enzyme activity, affecting the efficiency of drug conjugation processes and resulting in variations in drug efficacy and the risk of adverse effects
• Age


  • Neonates and infants have immature conjugation systems, which may not fully develop until several months or years after birth, resulting in slower drug metabolism and prolonged drug action
  • In elderly individuals, a decline in physiological function, including liver function, can affect the efficiency of drug metabolism, necessitating adjustments in drug dosing
• Liver Function


  Hepatic diseases such as cirrhosis or hepatitis can impair conjugation reactions, leading to decreased clearance of drugs from the body and increasing the risk of drug accumulation and toxicity
• Nutrition


  Malnutrition or specific nutritional deficiencies can affect the levels of cofactors necessary for the activity of Phase 2 enzymes, potentially impairing their function
• Genetic Variability


  Individuals have genetic variants that result in reduced or enhanced enzyme activity, categorizing them as poor or rapid metabolizers, respectively
• Age


  • Neonates and infants have immature conjugation systems, which may not fully develop until several months or years after birth, resulting in slower drug metabolism and prolonged drug action
  • In elderly individuals, a decline in physiological function, including liver function, can affect the efficiency of drug metabolism, necessitating adjustments in drug dosing
• Liver Function


  • Since the liver is the primary site for Phase 2 metabolism, hepatic diseases such as cirrhosis or hepatitis can impair conjugation reactions, leading to decreased clearance of drugs from the body and increasing the risk of drug accumulation and toxicity
• Nutritional Status


  • Malnutrition or specific nutritional deficiencies can affect the levels of cofactors necessary for the activity of Phase 2 enzymes, potentially altering the rate of drug metabolism
  • Certain dietary components can induce or inhibit Phase 2 enzymes, potentially affecting drug metabolism
• Broccoli and other cruciferous vegetables

  Contain compounds called glucosinolates, which are converted into bioactive compounds called isothiocyanates, including sulforaphane, that may have effects on phase 2 drug metabolism