Chemical Pathways of Drug Metabolism Phase 1 II reactions

Chemical Pathways of Drug Metabolism

  • Presenter: Sheeba Varghese Gupta, MPharm, PhD

  • Date: February 10, 2025

Learning Objectives

  • Explain basic concepts of metabolism.

  • Identify common CYP forms exhibiting polymorphism.

  • Differentiate between Phase I and II metabolism.

  • Identify reactions from Phase I and II metabolism.

  • Identify enzymes and cofactors responsible for Phase I and II metabolism.

  • Explain clinical significance of Phase I and II metabolism.

Drug Metabolism Overview

  • Two primary sites: Hepatic (liver) and Extra-Hepatic (brain, lungs, skin, heart, kidneys, GIT, blood).

  • Types of metabolism:

    • Microsomal: Involves enzymatic processes in the microsomal fraction of cells.

    • Non-microsomal: Enzymes outside the microsomal fraction that participate in metabolic processes.

Enzymes in Drug Metabolism: CYPs

  • Organ Location: Liver, kidneys, lungs, and intestine.

  • Cellular Location: Endoplasmic reticulum (ER).

  • Function: Catalyzes oxidation reactions.

  • Classification: Based on family, subfamily, and isoforms. Example: CYP3A4 (Cytochrome P450 Family).

Drug Metabolism Mechanism

  • Phase I Metabolism: Introduces polar functional groups to drugs, increasing water solubility.

    • Complete metabolic transformation may occur after Phase I or can proceed to Phase II.

  • Phase II Metabolism: Involves conjugation with endogenous molecules (amino acids, sulfates, glutathione) to further enhance water solubility. Exceptionally includes methylation and acetylation.

Phase I Reactions

  • Oxidation: 95% catalyzed by CYP enzymes; non-CYP enzymes also play a role.

    • Key Non-CYP enzymes: Alcohol dehydrogenase, aldehyde dehydrogenase, flavin-containing monooxygenase (FMO), xanthine oxidase, amine oxidase, aromatases.

    • Hydroxylation: Adding hydroxyl groups to aliphatic or aromatic structures. Enzyme examples: CYP2C8/ CYP2C9.

    • N-Oxidation & S-Oxidation: Transforming nitrogen and sulfur-containing substrates to oxides (catalyzed by FMO).

    • Dealkylation: Loss of alkyl groups from nitrogen, oxygen, or sulfur. Example: CYP2D6.

    • Deamination: Loss of primary amine groups to form ketones or acids, commonly seen in neurotransmitter metabolism; catalyzed by Monoamine Oxidases (MAO).

  • Reduction: Less common, involves CYP450 enzymes with NADPH, includes azo-reduction, nitro-reduction, and ketone reduction.

  • Hydrolysis: Transformation of drugs containing esters or amides. Esterases and amidases facilitate this reaction.

Phase II Reactions

  • Conjugation Reactions: Adds hydrophilic groups to handles formed in Phase I.

    • Glucuronic Acid Conjugation: Most common; glucuronides are generally less reactive than parent compounds and readily eliminated by kidneys.

    • Sulfate Conjugation: Frequently observed in steroid hormones, catecholamine neurotransmitters, bile acids, and phenolic drugs.

    • Glutathione Conjugation: Substitutes the electrophilic part of xenobiotics with glutathione, aiding in detoxification and functioning as a free radical scavenger.

    • Glycine Conjugation: Major pathway for carboxylic acids; this pathway is underdeveloped in newborns.

    • Methylation / Acetylation: While these reactions are Phase II processes, they tend to decrease water solubility (e.g., Acetyl CoA).

Case Study Discussion

  • Case involves a full-term male infant breastfed by a codeine-using mother.

  • Symptoms: Difficulty breastfeeding, lethargy, grey skin, reduced milk intake; led to death with elevated morphine levels in blood.

  • Analysis: Determine the reasons behind elevated morphine levels in the neonate, supported by metabolic explanations.