Phase 2 Drug Metabolism Reactions

Phase 2 Drug Metabolism Reactions

Introduction

  • Overview of Phase 2 Drug Metabolism.

Phase 2 Reactions

  • Conjugation Reactions: Involves the joining of a compound to a molecule.

  • Position in Metabolism: These reactions can occur either after or before Phase 1 reactions.

  • Outcome: Generally make compounds more water-soluble.

  • Genetic Variability: Many conjugation enzymes show polymorphisms, which is the existence of one or more forms of the same gene.

Examples of Phase 2 Reactions

  1. Glucuronidation

  2. Sulfation

  3. Acetylation

  4. Methylation

  5. Glutathione conjugation

  6. Amino acid conjugation

Phase 2 Reactions (continued)

  • D-Glucuronate, D-Acetate, D-Glycine, D-Sulfate, D-Glutathione, D-Methyl are important components for the conjugation processes.

  • Excretion and elimination are key outcomes of these metabolic changes.

Drug Metabolism - Specific Enzymatic Processes

1. Glucuronidation

  • Key Enzyme: UDP-glucuronosyl transferases (UGTs).

  • Location: Primarily in liver endoplasmic reticulum and intestinal epithelia.

  • Cofactor: UDP-glucuronic acid (UDPGA).

  • Preferred Substrates:

    • Hydroxyls (O-glucuronidation)

    • Amines (N-glucuronidation)

    • Carboxylic acids (Acyl glucuronidation)

Sequence of Glucuronidation

  • Step 1: Conjugate is formed inside the cell from UDP-glucuronic acid and hydroxylated drug (e.g., Salicylic acid).

    • Reactions leading to structures like D-glucuronate.

    • Importance: Ensures increased solubility and eventual excretion.

2. Sulfation

  • Key Enzyme: Sulfotransferases (SULTs).

  • Location: Found in liver cytosol.

  • Preferred Substrates: Hydroxyl groups (primarily phenolic compounds).

  • Cofactor: 3’-phosphoadenosine-5’-phosphosulfate (PAPS).

3. Acetylation

  • Key Enzyme: N-acetyltransferase (NAT).

  • Location: Predominantly in the liver.

  • Preferred Substrates: Primary amines.

  • Cofactor: Acetyl CoA.

  • Variability: Significant patient variability leading to fast and slow acetylators.

  • Impact on Drug Properties: Generally leads to an initial decrease in water solubility. Products may undergo hydrolysis before elimination.

Example: Acetylation of Isoniazid

  • Isoniazid (Antitubercular) is converted via N-acetyltransferase to N-acetylisoniazid and other metabolites, illustrating the acetylation process and its products.

4. Methylation

  • Key Enzymes: Methyltransferases (O-, N-, S-methyltransferases).

  • Preferred Substrates: Hydroxyls, amines, and thiols.

  • Cofactor: S-adenosyl methionine (SAM-e).

  • Outcome: Generally leads to decreased water solubility. Seen in neurotransmitters like norepinephrine and dopamine, as well as drugs of similar structures.

5. Amino Acid Conjugation

  • Process: Two-step pathway involving two enzymes.

  • Step 1: Activation of carboxylic acids by ATP and acetyl CoA, catalyzed by acyl CoA synthetases.

  • Step 2: Formation of a conjugate with glycine or glutamine, catalyzed by N-acyltransferases.

  • Outcome: Produces highly water-soluble products.

Glutathione Conjugation

Key Enzyme: Glutathione-S-transferase (GST)

  • Substrates: Generally electrophilic groups.

  • Importance: Critical for detoxifying environmental toxicants and chemical carcinogens.

Summary of Phase 2 Reactions

  • Importance of Water Solubility: Most reactions significantly increase water solubility but can sometimes decrease it.

  • Impact on Drug Activity: Can enhance drug activity in certain cases, like morphine and minoxidil.

  • Polymorphisms: Phase 2 enzymes exhibit significant genetic variability across different populations.

Induction of Drug-Metabolizing Enzymes

Induction Process

  • Definition: Increase in the levels of enzymatic activity through the activation of intracellular receptors.

  • Mechanism: 1. Drug enters the cell, 2. Binds to a nuclear receptor (e.g., pregnane X receptor (PXR)), 3. Forms a complex with retinoid X receptor (RXR) that binds DNA to promote transcription of CYP genes.

  • Example: Atorvastatin lineage involves its own metabolism induction through CYP3A4.

Selected Compounds That Induce CYP450s

  • Common Inducers: Include drugs and dietary components such as broccoli, phenobarbital, and tobacco smoke.

Inhibition of Drug-Metabolizing Enzymes

Types of Inhibition

  • Competitive Inhibition: Drugs bind actively and reversibly, affecting the enzyme's action.

  • Noncompetitive Inhibition: Binds allosterically, reversible, which can also impact enzyme activity.

  • Irreversible Inhibition: Requires new enzyme synthesis for activity to resume.

Selected Compounds That Inhibit CYPs

  • Common inhibitors include fluvoxamine, cimetidine, and ketoconazole.

Factors Influencing Drug Metabolism

Genetic Factors

  • Many polymorphisms exist among cytochrome P450s and phase 2 enzyme distributions.

  • Examples: CYP2C9, CYP2C19, CYP2D6, which demonstrate variability leading to slow or fast metabolizers.

Age, Gender, Diet, Disease, & Species Impacts

  • Age: Neonates have underdeveloped enzymes leading to specific conditions such as jaundice, while geriatrics experience reduced liver blood flow affecting drug clearance.

  • Gender Differences: Hormonal differences can lead to variations in drug metabolism rates, particularly noted with certain medications.

  • Diet: Foods and environmental toxins can induce or inhibit metabolism via their impact on liver enzymes or gut flora.

  • Disease Conditions: Liver disease can lead to significant impacts on metabolism and drug half-lives.

  • Species Variations: Differences in metabolizing enzyme pathways exist across species, with notable mention of how cats metabolize certain drugs poorly compared to humans.

Drug Transport Mechanisms

Overview of Transport Systems

  • Passive Transport: Lipophilic drugs may cross membranes easily; others need active transport.

  • Transport Proteins: Such as OATP for bringing drugs into cells, whereas P-glycoprotein facilitates drug egress.

Active Transport and Efflux Pump Dynamics

  • Importance of OATP and OAT: Transporting drugs from gut and liver, with implications for drug interactions and metabolism.

  • Role of P-Glycoprotein: Crucial for maintaining drug levels within cells and for their eventual elimination.

Thought Questions Summary

  • Multiple thought questions posed about the clinical implications of drug metabolism changes due to various patient conditions, highlighting the complexity of individualized medicine and metabolic profiles.