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PHASE II: Conjugation Reaction

PHASE II: Conjugation Reaction. R O S E L Y N A. N A R A N J O . CONJUGATION REACTION. Glucuronic acid conjugation Sulfate conjugation Conjugation with Glysine, Glutamine, and other AA

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PHASE II: Conjugation Reaction

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  1. PHASE II: Conjugation Reaction R O S E L Y N A. N A R A N J O

  2. CONJUGATION REACTION • Glucuronic acid conjugation • Sulfate conjugation • Conjugation with Glysine, Glutamine, and other AA • Glutathione or Mercapturic Acid Conjugation • Acetylation • Methylation

  3. CONJUGATION REACTION • Does not always produce hydrophilic or inactive metabolites • Form more polar and water soluble products • Enzymes attach small, polar and ionizable molecules (glucuronic acid, sulfate, glycine and glutamine) to the Phase I metabolites or to parent xenobiotics. • Conjugating group includes glucuronic acid, sulfate, methyl and acetyl groups • Regarded as a truly detoxifying pathway in drug metabolism

  4. GLUCURONIC ACID CONJUGATION • Glucuronidation is the most common conjugative pathway in drug metabolism for the following reasons: • Readily available supply of d-glucuronic acid (from glucose) • Numerous functional groups that combine enzymatically with glucuronic acid • Glucuronyl moiety, polar hydoxyl groups which greatly increases water solubility when attached to the xenobiotics substrate. • Combine with chemically reactive compound to form to prevent damage to important biomolecules

  5. GLUCURONIC ACID • Formation of ß-glucuronides involves two steps: • synthesis of an coactivated enzyme (uridine-5’diphopho, ∂-D glucoronic acid (UDPGA) • Transfer of the glucuronyl group from UDPGA to an appropriate substrate.

  6. FUNCTIONAL GROUPS THAT UNDERGO GLUCURONIDATION A. OXYGEN GLUCURONIDES a.1 Hydroxyl Compounds • Phenols: morphine, acetaminophen, p-hydroxyphenytoin • Alcohols: trichloroethanol, chloramphenicol, propranolol • Enols: 4-hydroxycoumarin • N-Hydroxyamides: N-hydroxydapsone, N-hydroxy-2-acetylaminoflourene

  7. FUNCTIONAL GROUPS THAT UNDERGO GLUCURONIDATION a.2 Carbonyl Compounds • Aryl acids: benzoic acids, salicylic acid • Arylalkyl acids: Naproxen, Fenoprofen B. NITROGEN GLUCURONIDES - Arylamines: 7-amino-5-nitroindazole • Arylamines: desipramine • Amides: meprobamate • Sulfonamides: Sulfisoxazole • Tertiary Amines: Cyproheptadine, tripelennamine

  8. FUNCTIONAL GROUPS THAT UNDERGO GLUCURONIDATION C. SULFUR GLUCURONIDES • Sulfhydryl groups: methimazole, propylthiouracil, diethylthiocarbamic acid D. CARBON GLUCURONIDES -3,5Pyrazolidinedione: phenylbutazone, sulfinpyrazone

  9. GLUCURONIDATION PROCESS SHOWING THE SITE OF GLUCURONIDES ATTACHMENT TO THE METABOLITE • MORPHINE(INSERT STRUCTURE) • ACETAMINOPHEN • PROPRANOLOL • CHLORAMPHENICOL

  10. SULFATE CONJUGATION • Process occurs primarily with phenols, alcohols, aromatic amines, and N-hydoxy compounds. • The body uses portion of sulfate pool to conjugate emdogenous compounds such as steroids, heparin, chondroitin, catecholamine, and thyroxine. • Involves the activation of inorganic sulfate to its co-enzyme.

  11. SULFATE CONJUGATION • Phenols are main groups of substrates that undergo conjugation. • Drug containing phenolic moiety are often susceptible to sulfate formation.

  12. Conjugation with glycine, glutamine, and other Amino Cids • Conjugates carboxylic acids particularly aromatic and arylaklyl acids. • Example: (insert photo) • Benzoin Acid • Salicylic acid

  13. Conjugation with GSH or Mercapturic acid • Important pathway for detoxifying chemically reactive electrophilic compounds. • Called glutamyl-cysteinylglycine (found in most tissues) • Process involves enzymatic cleavage of two amino acid – glutamic acid and glycine) • Its conjugation is catalyzed by an enzyme known as glutathione S-transferase. • Degradation of GSH is due to renal and hepatic microsomal enzymes

  14. Conjugation with GSH or Mercapturic acid • Example: insert structure of brompheniramine Haloperidol, Diphenhydramine

  15. ACETYLATION • Constitutes a metabolic route for drugs containing primary amino groups, which includes the following: • Aromatic amines (ArNH2) • Sulfonamides (H2NC6H4SO2NHR) • Hydrazines (NHNH2 ) • Hydrazides (-CONHNH2) • Aliphatic amines

  16. ACETYLATION • Derivatives formed from these amino functionalities are inactive and non-toxic. • Its primary function is the termination of pharmacological activity and detoxification • Less water solubility • Acetyl group used is acetyl-CoA

  17. METHYLATION • Inactivation of physiologically active biogenic amines • Does not convert metabolites to become more water soluble except when it creates a quaternary ammonium derivative. • Most of the products end up pharmacologically inactive

  18. METHYLATION • Foreign compounds that undergo methylation includes: • Cathecols,phenols, amines and N- heterocyclic and thiol compounds. • Anihypertensive drugs (methyldopa) • Antiparkinsonism agent (levodopa) • Norephenephrine and Dopamine

  19. FACTORS THAT AFFECTS DRUG METABOLISM

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