Drug Metabolism Overview

Drug Metabolism

• Metabolism is the process by which drugs undergo transformations by enzymes.
• Drugs generally start lipophilic and are transformed into hydrophilic metabolites, becoming more excretable.
• Increased water solubility results in increased renal excretion and decreased tubular reabsorption.
• Alcohol consumption results in significant increases in ethanol metabolism and clearance of other drugs eliminated by the cytochrome P450 system.
• Genetic deficiencies in the ALDH enzyme, common in East Asians, are linked to "Genetic Disulfiram".

Phase I Metabolism

• Generally involves oxidation, reduction, or hydrolysis reactions.
• Often introduces polar groups like hydroxyl, carboxyl, or amine.
• Can generate more reactive metabolites.

Phase II Metabolism

• Involves conjugation reactions where a hydrophilic group is conjugated to the molecule, giving a water-soluble product.
• Often, phase I metabolism provides a conjugation site (e.g., OH).

Main Conjugation Reactions:

• Glutathione Conjugation: Common for aromatic nitro- and halogenated compounds.
• Glucuronic Acid Conjugation: Most common form of conjugation, common for drugs with -OH, -COOH, -NH2 groups.
• Sulfate Conjugation: Common for phenols.
• Glycine Conjugation: Common for drugs with -COOH groups.
• Acetylation: Common for drugs with -NH2 groups.

Metabolism and Toxicity

• Paracetamol: Normally undergoes glucuronidation and sulfation, making up 95% of excreted metabolites.
• Hepatotoxicity: Occurs because 5% of paracetamol is oxidized to benzoquinoneimine, a highly reactive substance.
• When glutathione stores are depleted: Benzoquinoneimine combines with hepatic proteins and causes liver injury.
• Alcohol abuse and paracetamol toxicity: Ethanol induces CYP1A2, CYP2E1, and CYP3A4, which oxidize paracetamol to benzoquinonamine.
• Alcohol abusers have higher levels of these enzymes: This leads to increased conversion of paracetamol to benzoquinonamine, increasing risk of toxicity at lower doses.

Cytochrome P450

• Family name: CYP (Cytochrome P450)
• Subfamily: Specific protein
• Different allelic forms: Account for person-to-person variability in drug metabolism.
• Knowledge of the P450 system: Essential for understanding drug metabolism and drug interactions.

Learning Objectives:

• Define pharmacokinetics and describe the main purpose of drug metabolism.
• Describe the types of reactions involved in phase I and phase II drug metabolism with examples.
• Describe the metabolism of ethanol and the mechanism of action of disulfiram.
• Describe the metabolism of aspirin and paracetamol and explain why some drugs are toxic at high doses.
• Define prodrugs and recall situations in which these are used.
• Describe drug-drug interactions.

Pharmacokinetics:

“What the body does to the drug”

• Key components:
  • Administration
  • Distribution
  • Metabolism
  • Elimination

Prodrugs:

• Pharmacologically inert precursor to an active drug.
• Activation usually involves a phase I reaction.

Reasons to use a prodrug:

• Overcome drug instability
• Site-specific drug delivery
• Improve physicochemical properties
• Prolonged drug release
• Encourage patient acceptance

Prodrug example:

• Cefamandole sulfate: A broad-spectrum antibiotic that is difficult to purify and unstable.
• Cefamandole sulfate-methanoic acid ester: A stable prodrug formed by reacting cefamandole sulfate with methanoic acid. It is cleaved by esterases in the blood to release the active drug.

Site-specific drug delivery example:

• Sulfasalazine: The drug of choice for ulcerative colitis.
• 5-aminosalicylic acid (5-ASA): The active therapeutic moiety.
• Azo linkage: 5-ASA is linked to sulfapyridine by an azo linkage.
• Azoreductases: These enzymes break down the azo linkage in the colon, releasing 5-ASA for targeted delivery.

Drug-drug interactions:

• CYP3A4/5 and UGT: Involved in the metabolism of more than 75% of drugs in use.
• Person-person variation in CytP450 genes: Responsible for many unexpected adverse drug reactions.

Pharmacokinetics

• Pharmacokinetics is the study of how drugs move into, around and out of the body.
• It focuses on what the body does to the drug.
• It comprises four key components:
  • Administration
  • Distribution
  • Metabolism
  • Elimination

Drug Metabolism

• Drug metabolism is the process by which drugs undergo transformations catalyzed by enzymes.
• The products of these transformations are called metabolites
• Drug metabolism generally converts lipophilic drugs into hydrophilic metabolites, which are easier to excrete.
• Many of the enzymes involved in drug metabolism have broad substrate specificity, meaning they can act on a variety of drugs.

Phase I Reactions

• Phase I drug metabolism typically involves oxidation, reduction, or hydrolysis reactions.
• Examples:
  • Oxidative dealkylation: Codeine is de-alkylated to morphine.
  • Reduction: Chloramphenicol undergoes reduction.
  • Hydrolysis: Aspirin is hydrolyzed to salicylate and acetate.
• The enzymes involved in these reactions are often referred to as mixed-function oxidases, or cytochrome P450 enzymes.

Phase II Reactions

• Phase II drug metabolism involves conjugation reactions where a drug molecule is coupled with a polar molecule.
• This process typically increases the water solubility of the drug, facilitating excretion.
• Examples:
  • Glucuronidation
  • Sulfation
  • Acetylation
  • Methylation

Ethanol Metabolism

• Most ethanol is metabolized by the liver.
• Main enzymes involved:
  • Alcohol dehydrogenase (ADH): Converts ethanol to acetaldehyde.
  • Aldehyde dehydrogenase (ALDH): Converts acetaldehyde to acetate.
• Disulfiram: Is an irreversible inhibitor of ALDH.
• This leads to an accumulation of acetaldehyde and causes unpleasant side effects such as flushing, nausea, vomiting, dizziness, and headache.

Prodrugs

• A prodrug is a pharmacologically inactive precursor to an active drug.
• Activation of a prodrug generally involves a phase I reaction.
• They are often utilized to:
  • Overcome drug instability
  • Achieve site-specific drug delivery
  • Improve physicochemical properties
  • Prolong drug release
  • Encourage patient acceptance

Drug-Drug Interactions

• Drug-drug interactions can occur when two or more drugs are taken simultaneously.
• One drug can influence the metabolism of another drug, leading to altered plasma concentrations and potential adverse effects.
• The cytochrome P450 enzymes are highly involved in drug-drug interactions.
• This is a primary reason for monitoring patients' responses to drug therapy and implementing individual drug adjustments.

CYP3A4/5 and UGT Enzymes

• These enzymes are involved in the metabolism of over 75% of drugs in use.
• They play a crucial role in the detoxification and elimination of a wide range of medications.
• Individual variations in these enzyme activities can lead to significant differences in drug responses among patients.