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Chemistry

Metabolism, Excretion

Understanding drug metabolism and excretion processes is critical in therapeutic drug monitoring (TDM)

Drug Metabolism

  • Definition: The process by which the body chemically alters a drug, often to facilitate its elimination
  • Primary Site of Metabolism: Liver
  • Other Sites: Kidneys, intestines, lungs, and plasma
  • Purpose of Metabolism
    • Convert lipid-soluble drugs into more water-soluble metabolites, facilitating their excretion in the urine
    • Inactivate drugs to terminate their pharmacological effects
    • Activate prodrugs into active metabolites
  • Phases of Metabolism
    • Phase I Reactions: Introduce or expose a functional group on the drug molecule through oxidation, reduction, or hydrolysis
    • Phase II Reactions: Conjugate a polar molecule to the drug molecule, such as glucuronic acid, sulfate, or glutathione

Phase I Metabolism

  • Oxidation
    • Addition of oxygen or removal of hydrogen atoms from the drug molecule
    • Enzymes involved: Cytochrome P450 (CYP) enzymes
    • Examples of reactions: Hydroxylation, epoxidation, N-oxidation, S-oxidation
  • Reduction
    • Addition of hydrogen atoms or electrons to the drug molecule
    • Enzymes involved: Reductases
    • Examples of reactions: Reduction of nitro groups, azo groups, and carbonyl groups
  • Hydrolysis
    • Addition of water to break a chemical bond
    • Enzymes involved: Esterases, amidases, peptidases
    • Examples of reactions: Hydrolysis of esters, amides, and peptides

Phase II Metabolism

  • Glucuronidation
    • Addition of glucuronic acid to the drug molecule
    • Enzymes involved: UDP-glucuronosyltransferases (UGTs)
    • Results in highly water-soluble metabolites that are easily excreted in the urine
  • Sulfation
    • Addition of a sulfate group to the drug molecule
    • Enzymes involved: Sulfotransferases (SULTs)
    • Results in water-soluble metabolites that are easily excreted in the urine
  • Acetylation
    • Addition of an acetyl group to the drug molecule
    • Enzymes involved: N-acetyltransferases (NATs)
    • Genetic polymorphisms in NAT enzymes can affect drug metabolism
  • Glutathione Conjugation
    • Addition of glutathione to the drug molecule
    • Enzymes involved: Glutathione S-transferases (GSTs)
    • Important for detoxifying reactive metabolites
  • Methylation
    • Addition of a methyl group to the drug molecule
    • Enzymes involved: Methyltransferases
    • Can either activate or inactivate drugs

Cytochrome P450 (CYP) Enzymes

  • Definition: A superfamily of heme-containing monooxygenases that catalyze the oxidation of many drugs and endogenous compounds
  • Location: Primarily in the liver, but also present in other tissues
  • Importance in Drug Metabolism: Responsible for the metabolism of approximately 75% of clinically used drugs
  • Key CYP Enzymes
    • CYP3A4: Metabolizes the largest number of drugs
    • CYP2D6: Metabolizes many psychiatric and cardiovascular drugs
    • CYP2C9: Metabolizes nonsteroidal anti-inflammatory drugs (NSAIDs) and warfarin
    • CYP2C19: Metabolizes proton pump inhibitors (PPIs) and clopidogrel
    • CYP1A2: Metabolizes caffeine and theophylline

Factors Affecting Drug Metabolism

  • Genetic Factors
    • Genetic polymorphisms in drug-metabolizing enzymes can affect drug metabolism
    • Individuals can be classified as poor metabolizers, intermediate metabolizers, extensive metabolizers, or ultra-rapid metabolizers
  • Age
    • Infants have immature metabolic enzyme systems
    • Elderly individuals may have decreased liver function and reduced enzyme activity
  • Disease States
    • Liver disease: Reduces metabolic enzyme activity
    • Kidney disease: Affects drug clearance and can lead to drug accumulation
    • Heart failure: Reduces blood flow to the liver and kidneys, impairing drug metabolism and excretion
  • Drug Interactions
    • Enzyme Inducers: Increase the activity of metabolizing enzymes, leading to decreased drug levels
    • Enzyme Inhibitors: Decrease the activity of metabolizing enzymes, leading to increased drug levels
  • Diet and Environmental Factors
    • Grapefruit juice: Inhibits CYP3A4
    • Smoking: Induces CYP1A2
    • Alcohol: Can induce or inhibit certain enzymes
  • Gender
    • Differences in hormone levels and body composition can affect drug metabolism

Drug Excretion

  • Definition: The process by which the body eliminates a drug or its metabolites
  • Primary Routes of Excretion
    • Kidneys: Most drugs are excreted in the urine
    • Liver: Some drugs are excreted in the bile and eliminated in the feces
  • Other Routes: Lungs, sweat, saliva, breast milk
  • Renal Excretion
    • Glomerular Filtration: Drugs and small molecules are filtered from the blood into the renal tubules
      • Only unbound (free) drug can be filtered
    • Tubular Secretion: Active transport of drugs from the blood into the renal tubules
      • Can be affected by drug interactions
    • Tubular Reabsorption: Passive or active transport of drugs from the renal tubules back into the blood
      • Lipid-soluble drugs are more readily reabsorbed
      • Urine pH can affect the reabsorption of weak acids and bases
  • Biliary Excretion
    • Drugs and metabolites are transported from the liver into the bile
    • Bile is secreted into the small intestine and eliminated in the feces
    • Some drugs undergo enterohepatic circulation, where they are reabsorbed from the intestine back into the blood
  • Clearance (CL)
    • A measure of the body’s efficiency in eliminating a drug from the body
    • Total Clearance: Sum of all clearance pathways (renal, hepatic, and other)
    • Renal Clearance: The volume of plasma from which a drug is completely removed by the kidneys per unit of time
    • Hepatic Clearance: The volume of plasma from which a drug is completely removed by the liver per unit of time
  • Factors Affecting Excretion
    • Renal Function: Glomerular filtration rate (GFR), tubular secretion, and tubular reabsorption affect renal drug excretion
    • Liver Function: Bile flow and hepatic metabolism affect biliary drug excretion
    • Drug Properties: Molecular size, ionization, and protein binding affect excretion
    • Drug Interactions: Some drugs can affect the excretion of other drugs

Clinical Significance

  • Drug-Drug Interactions (DDIs)
    • Knowledge of metabolic pathways and drug excretion mechanisms is crucial for predicting and managing DDIs
    • Enzyme inducers and inhibitors can significantly alter drug levels, leading to therapeutic failure or toxicity
  • Pharmacogenomics
    • Genetic testing can identify individuals with variations in drug-metabolizing enzymes
    • Personalized dosing recommendations can be made based on an individual’s genotype
  • Dosage Adjustments in Patients with Renal or Hepatic Impairment
    • Patients with impaired renal or hepatic function may require lower doses or less frequent dosing to avoid drug accumulation and toxicity
  • Therapeutic Drug Monitoring (TDM)
    • TDM is used to optimize drug therapy by monitoring drug concentrations and adjusting doses based on individual patient factors
    • TDM can help ensure that drug levels are within the therapeutic range and minimize the risk of toxicity

Key Terms

  • Drug Metabolism: The process by which the body chemically alters a drug
  • Enzyme Induction: Increased activity of drug-metabolizing enzymes
  • Enzyme Inhibition: Decreased activity of drug-metabolizing enzymes
  • Cytochrome P450 (CYP) Enzymes: A superfamily of heme-containing monooxygenases
  • Prodrug: An inactive drug that is metabolized to an active metabolite
  • Drug Excretion: The process by which the body eliminates a drug or its metabolites
  • Glomerular Filtration: The process by which drugs and small molecules are filtered from the blood into the renal tubules
  • Tubular Secretion: The active transport of drugs from the blood into the renal tubules
  • Tubular Reabsorption: The transport of drugs from the renal tubules back into the blood
  • Biliary Excretion: The excretion of drugs and metabolites from the liver into the bile
  • Enterohepatic Circulation: The reabsorption of drugs from the intestine back into the blood
  • Clearance (CL): A measure of the body’s efficiency in eliminating a drug from the body
  • Drug-Drug Interactions (DDIs): The interactions between two or more drugs that can affect their absorption, distribution, metabolism, or excretion
  • Pharmacogenomics: The study of how genes affect a person’s response to drugs
  • Therapeutic Drug Monitoring (TDM): Measurement of drug concentrations to optimize therapy
  • Genetic Polymorphism: Variation in the DNA sequence among individuals