Drug Metabolism: Phase I & II Reactions

Review of Phase I Metabolism

• Drugs and xenobiotics are eliminated
• Functionalization reactions take place
• Polar functional groups (hydroxyl, carboxylic acids, amine, thiols) get added
• Oxidation, Hydroxylation, and Reduction happen
• Accomplished via direct introduction and modification/unmasking

Notes on Functionalization Reactions

• Centers around functionalization
• A lipophilic drug is transformed into a hydrophilic drug for excretion
• Direct introduction includes hydroxylation
• Modification/Unmasking includes reduction
• Some compounds need conjugation before elimination

Phase II or Conjugation Reactions

• Small, polar, and ionizable endogenous molecules attach, including:
  • Glucuronic acid
  • Sulfate
  • Glycine, Glutamine
• The goal is to make drugs hydrophilic and inactive for excretion/inactivation
• Not all cases require high water solubility, inactivation can occur through acetylation/methylation

Conjugation Reactions

• Attachment of glucuronic acid
• Addition of a sulfate group
• Introduction of an acetyl group
• The addition of a methyl group
• Acetylation and methylation are involved in drug inactivation

Conjugated Products

• Conjugated products are water-soluble and readily excreted
• Conjugated products are biologically inactive and nontoxic

Methylation and Acetylation

• Don't increase water solubility
• Main activity: to attenuate or terminate pharmacological activity
• Phase II reactions are detoxifying pathways

Importance of GSH (Glutathione)

• Combines with chemical compounds
• Prevents damage to biomacromolecules (DNA, RNA, proteins)
• Serves in the body as an antioxidant

Phase 2

• Endogenous compounds going through conjugation include
  • Bilirubin
  • Steroids
  • Catecholamines
  • Histamine
• Actions are controlled by transferase enzymes

Glucuronic Acid Conjugation

• There is a readily available supply of D-glucuronic acid
• Numerous functional groups can enzymatically combine with glucuronic acid
• Glucuronyl increases water solubility when ionizing with carboxylate and polar hydroxyl groups attach to xenobiotic substrates
• This pathway attaches a B-glucuronide to xenobiotics/drugs
• B-glucuronide drugs are more likely metabolized via glucuronic acid conjugation
• XR: xenobiotics/drugs parts in B-glucuronide will attach activate coenzymes
  • UDPGA
• The substrate includes drugs/xenobiotics

Types of Glucuronides

• Oxygen Glucuronides are the first classification of compounds forming glucuronic acid conjugation
• Hydroxyl compounds react to functional groups of phenolic hydroxyls:
  • Morphine
  • Acetaminophen
  • Hydroxy phenytoin

Other Substrates of Glucuronidation

• Phenols: morphine, acetaminophen, p-hydroxyphenytoin
• Alcohols: Tricholoroethanol, chloramphenicol, propranolol
• Enols: 4-hydroxycoumarin
• N-Hydroxyamines: N-Hydroxydapsone
• N-Hydroxyamides: N-Hydroxy-2-acetylaminofluoren
• Aryl acids: benzoic acid, salicylic acid
• Arylalkyl acids: naproxen, fenoprofen

Alcohol + o-Glucuronide conjugation

• Propranolol undergoes phase 2 (propranolol glucronide) or phase 1 (N-desisopropylpropranolol results to Naphthoxylactic acid)

Regulation of metabolic pathways

• Drugs don't only use 1 pathway
• If phases 1 and 2 haven't finished, they can continue as processes
• Phase 1 may happen instead of phase 2, or vice versa

Carboxyl & Glucuronic acid Conjugation

• Benzoic acid and salicylic acids are aryl acids Glucuronidation of Nitrogen is less prevalent in the body, and glucuronic acid attaches there at the Carbon atom

Transferase Notes

-Example: catecholamines like dopamine

• Catechol-O-Methyltransferase, or COMT, is particularly involved in levadopa reactions and degradation

Drugs & Reactions to Sulfate

• Transfers O-sulfate to some N-hydroxy
• Produces toxic metabolites and conjugates within some phenols
• They can be combined with Glucuronidation

Amino acids & Reactions

• Use glycine and glutamine
• Mammalian systems link with carboxylic acids, aromatic and aryl acids
  • glycine is a mammal
  • glutamine is a human

GSH or Mercapturic Acid Conjugates

• The focus is to detoxify chemically reactive electrophilic compounds
• Glutathione protects cell components versus chemical species
• There is the assistance of a group of nucleophilic sulfhydrls in reactions with electron-deficient compounds
• In these reactions, glutathione acts as an antioxidant in the body, preventing cell damage

Important Note

• N-acyltransferase is the enzyme makes glycine conjugate and glutamine conjugate with reactions

Acetylation

• An important metabolic route for primary amino groups in: -Primary aromatic amines -Sulfonamides -Hydrazine -Hydrazides -Primary aliphatic amines
• The amide derivatives made w/acetylated amino functionalities are generally inactive and non-toxic
• The primary function = terminate pharmacological activity

Acetylation Polymorphism

• Ethnic groups determine rate of rapid vs fast acetylators
• Rapid acetylators can have inadequate response to drugs
• Europeans + Egyptians mainly consisted of slow acetylators with high reaction to drugs *due to accumulation
• Isoniazid (I) - hinders Phenytoin (PHT) & effects vary w/acetylation
• PHT leads to accumulation of drugs & interaction; great adverse events

Effects with Slower Acetylation

adverse:

• peripheral neuritis
  • Drug-induced systemic Lupus

Isoniazid: Fast/Slow Acetylation

• More likely to promote Isoniazid-associated hepatitis

Methylation-O + significant Drugs

• (S) (-) @-methyldopa; Aldomet
• (-) Dopa; Levodopa
• Isoproterenol; Isuprel
• Dobutamine; Dobutrex
• Important notes for the above includes that selectivity of Methyl O occurs for select molecules & should be consistent with all elements of benzenes

Glucuronidation in Neonates

• If too low rate, toxic effects in body can occur due to unabsorbed toxic build ups = toxicity

Drugs That Can Cause Reaction

• Some can trigger red skin
• Others are involved with high reactions
• Look for high levels or effects of glucuronide reaction
• Watch out for signs of enzyme problems
• Glucuronidation in body = very important