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Chemistry

Metabolism, Excretion

Understanding the processes of metabolism and excretion is crucial in toxicology

Drug Metabolism

  • Definition: The process by which the body chemically alters a toxic substance, often to facilitate its elimination
  • Primary Site of Metabolism: Liver
  • Other Sites: Kidneys, intestines, lungs, and plasma
  • Purpose of Metabolism
    • Convert lipid-soluble toxic substances into more water-soluble metabolites, facilitating their excretion in the urine
    • Detoxify by converting toxic substances into less harmful metabolites
    • Bioactivation: Convert relatively harmless substances into more toxic metabolites
  • Phases of Metabolism
    • Phase I Reactions: Introduce or expose a functional group on the toxic substance molecule through oxidation, reduction, or hydrolysis
    • Phase II Reactions: Conjugate a polar molecule to the toxic substance molecule, such as glucuronic acid, sulfate, or glutathione

Phase I Metabolism

  • Oxidation
    • Addition of oxygen or removal of hydrogen atoms from the toxic substance 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 toxic substance 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 toxic substance 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 toxic substance 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 toxic substance molecule
    • Enzymes involved: N-acetyltransferases (NATs)
    • Genetic polymorphisms in NAT enzymes can affect the metabolism of some toxic substances
  • Glutathione Conjugation
    • Addition of glutathione to the toxic substance molecule
    • Enzymes involved: Glutathione S-transferases (GSTs)
    • Important for detoxifying reactive metabolites, such as those formed during acetaminophen metabolism
  • Methylation
    • Addition of a methyl group to the toxic substance 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, toxins, and endogenous compounds
  • Location: Primarily in the liver, but also present in other tissues
  • Importance in Toxicology: Responsible for the metabolism of many toxic substances
  • Key CYP Enzymes
    • CYP3A4: Metabolizes the largest number of drugs and toxins
    • CYP2D6: Metabolizes many psychiatric and cardiovascular drugs
    • CYP2C9: Metabolizes nonsteroidal anti-inflammatory drugs (NSAIDs) and warfarin
    • CYP2E1: Metabolizes ethanol, acetaminophen, and some volatile organic compounds

Factors Affecting Drug Metabolism

  • Genetic Factors
    • Genetic polymorphisms in drug-metabolizing enzymes can affect the rate of 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
  • Drug Interactions
    • Enzyme Inducers: Increase the activity of metabolizing enzymes, leading to decreased levels of toxicant
    • Enzyme Inhibitors: Decrease the activity of metabolizing enzymes, leading to increased levels of toxicant
  • Diet and Environmental Factors
    • Grapefruit juice: Inhibits CYP3A4
    • Smoking: Induces CYP1A2
  • Gender
    • Differences in hormone levels and body composition can affect drug metabolism

Excretion

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

Clinical Significance

  • Understanding of Metabolism and Excretion Is Crucial for
    • Predicting the toxicity of substances
    • Assessing individual susceptibility to toxic effects
    • Developing effective treatments for poisoning
    • Designing strategies for preventing exposure to toxic substances
  • Altered Drug Metabolism Can Affect Toxicity * Enzyme inducers can decrease toxicant concentrations * Enzyme inhibitors can increase toxicant concentrations
  • Pharmacogenomics
    • Genetic testing can determine specific treatment to detox or remove the substance from the system
  • Dosage Adjustments in Patients with Renal or Hepatic Impairment * Knowing kidney or liver capabilities will allow for proper dosage adjustments
  • Therapeutic Drug Monitoring (TDM) * Some drugs may be used as treatments

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
  • Genetic Polymorphism: Variation in the DNA sequence among individuals
  • Bioactivation: Metabolic activation of a substance to become toxic