Drug Metabolism

• Drug metabolism


  The biochemical process by which the body chemically alters drugs or xenobiotics to facilitate their elimination from the body
• Drug metabolism


  Involves a series of enzymatic reactions primarily occurring in the liver, although other organs such as the intestine, kidney, and lungs also contribute
• Goals of drug metabolism

  • Increase the water solubility of drugs to facilitate their excretion
  • Decrease their pharmacological activity
  • Convert them into metabolites that are more easily eliminated from the body
• Factors influencing drug metabolism

  • Genetic factors/genetic polymorphisms
  • Environmental factors
  • Drug interactions
  • Physiologic conditions
  • Drug dosage regimen
• Genetic polymorphisms


  Variations in drug-metabolizing enzymes, such as CYP450 enzymes, that can lead to interindividual variability in drug metabolism rates and responses
• Environmental factors


  Diet, exposure to toxins, and lifestyle habits that can modulate enzyme activity and affect drug metabolism
• Drug interactions


  When the presence of one drug alters the metabolism of another drug, leading to changes in its pharmacokinetics and pharmacodynamics
• Physiologic conditions


  Age, sex, pregnancy, and disease states that can impact enzyme activity and influence drug metabolism rates
• Drug dosage regimen


  The frequency and dosage of medication administration can affect enzyme induction or inhibition, thereby influencing drug metabolism rates and therapeutic outcomes
• Hepatic enzyme involved in the biotransformation of drugs

  • The liver, primarily through oxidation, reduction, hydrolysis, and conjugation reactions, metabolizes drugs
  • Oxidation and reduction are facilitated by monoxygenase enzymes, specifically mixed-function oxidases (MFOs), located in hepatic parenchymal cells associated with the endoplasmic reticulum
• Mixed-function oxidase (MFO) enzymes

  Require reduced NADPH, molecular oxygen, cytochrome P-450, NADPH-cytochrome P-450 reductase, and phospholipid for their function
• Cytochrome P-450


  • A heme protein with iron protoporphyrin IX as the prosthetic group, serves as both an oxygen- and substrate-binding locus for drugs and endogenous substrates
  • Lipid-soluble drugs bind to cytochrome P-450, leading to their oxidation or reduction
  • Consists of closely related isoenzymes (isozymes) with varying amino acid sequences and drug specificity
• CYP monooxygenase enzyme system

  Includes cytochrome P450, catalyzes the biotransformation of both drugs and endogenous compounds like steroids, present in tissues beyond the liver, including the kidney, GI tract, skin, and lungs
• Other enzymatic oxidation reactions not involving the CYP monooxygenase system


  • Monoamine oxidase (MAO)
  • Alcohol and aldehyde dehydrogenase
  • Xanthine oxidase
• Monoamine oxidase (MAO)


  Deaminates endogenous substrates including neurotransmitters
• Alcohol and aldehyde dehydrogenase


  Metabolize ethanol
• Xanthine oxidase

  • Converts hypoxanthine to uric acid
  • Drug substrates include theophylline and 6-mercaptopurine, and allopurinol serves as both a substrate and inhibitor
• Drug biotransformation reactions


  • Hepatic biotransformation enzymes facilitate the inactivation and elimination of drugs that aren't easily cleared via the kidneys
  • Most drug metabolites are more polar than the parent compound, aiding in quicker elimination
  • Polar metabolites are less likely to be reabsorbed by renal tubular cells, leading to faster excretion in urine compared to lipid-soluble drugs
  • The nature of the drug and its route of administration influence the type of metabolite formed
• Examples of drug biotransformation

  • Isoproterenol forming a sulfate conjugate orally but a 3-O-methylated metabolite intravenously
  • Azo drugs like sulfasalazine undergoing cleavage by intestinal microflora, producing absorbable metabolites like 5-aminosalicylic acid and sulfapyridine
• Drug biotransformation


  Can be categorized based on metabolite pharmacologic activity or biochemical mechanism, typically resulting in the formation of pharmacologically inactive, polar metabolites

  
• Prodrugs


  Inactive or less active chemical derivatives of drugs that require biotransformation in the body to become pharmacologically active compounds
• Purpose of prodrugs


  • Enhance drug absorption, distribution, metabolism, and reduce side effects
• Activation mechanisms of prodrugs

  Enzymatic hydrolysis, oxidation, reduction, or conjugation processes that convert the prodrug into its active form
• Examples of prodrugs


  • Codeine (converted to morphine)
  • Enalapril (converted to enalaprilat)
  • Valacyclovir (converted to acyclovir)
• Advantages of prodrugs


  • Improved bioavailability
  • Targeted drug delivery
  • Enhanced stability
• Clinical applications of prodrugs

  Widely used in pharmaceuticals to optimize drug therapy, utilized in various therapeutic areas including pain management, cardiovascular diseases, infectious diseases, and cancer treatment
• Pathways of drug biotransformation

  • Phase I reactions (functionalization)
  • Phase II reactions (conjugation)

  
• Phase I reactions (functionalization)

  • Oxidation
  • Reduction
  • Hydrolysis
• Phase II reactions (conjugation)

  • Conjugations

  
• Some drugs mimic natural biochemical molecules and utilize metabolic pathways for normal body compounds
• Examples of drugs utilizing normal metabolic pathways

  • Isoproterenol methylated by catechol O-methyl transferase (COMT)
  • Amphetamine deaminated by monoamine oxidase (MAO)
• Phase I biotransformation reactions

  • Typically occur first and introduce or expose functional groups on drug molecules
  • Examples include aromatic hydroxylation, demethylation, and hydrolysis of esters
  • Some compounds form reactive intermediates like epoxides during hydroxylation, which can lead to liver necrosis or cancer
• The biotransformation of salicylic acid demonstrates the variety of metabolites that can be formed, including direct conjugation
• Natural


  Biochemical molecules and utilize metabolic pathways for normal body compounds
• Examples of natural biochemical molecules

  • Isoproterenol methylated by catechol O-methyl transferase (COMT)
  • Amphetamine deaminated by monoamine oxidase (MAO)
• PHASE 1 REACTIONS, "FUNCTIONALIZATION"


  1. Phase I biotransformation reactions introduce or expose functional groups on drug molecules

  2. Examples include aromatic hydroxylation of phenylbutazone to form oxyphenbutazone, and demethylation of codeine to form morphine

  3. Hydrolysis of esters, like aspirin or benzocaine, produces more polar products such as salicylic acid and p-aminobenzoic acid

  4. Some compounds, like acetaminophen and benzo[a]pyrene, form reactive intermediates like epoxides during hydroxylation, which can lead to liver necrosis or cancer

  5. The biotransformation of salicylic acid demonstrates the variety of metabolites that can be formed, including direct conjugation without prior phase I reaction
• PHASE 2 REACTIONS, "CONJUGATIONS"

  1. Phase II or conjugation reactions occur after a polar constituent is revealed or placed into the molecule

  2. Common examples include conjugation of salicylic acid with glycine to form salicyluric acid or with glucuronic acid to form salicylglucuronide

  3. Conjugation reactions utilize conjugating reagents derived from biochemical compounds involved in metabolism of carbohydrates, fats, and proteins

  4. These reactions involve high-energy forms of conjugating agents, such as UDPGA, acetyl CoA, PAPS, or SAM, which combine with the drug in the presence of transferase enzymes

  5. Some conjugation reactions may show limited capacity at high drug concentrations, leading to nonlinear metabolism

  6. Enzyme activity typically follows first-order kinetics at low drug concentrations but may demonstrate zero-order kinetics at high doses

  7. Glucuronidation reactions have high capacity and may exhibit nonlinear kinetics at very high drug concentrations

  8. Other conjugation pathways like glycine, sulfate, and glutathione may show lesser capacity and nonlinear kinetics at therapeutic drug concentrations due to factors such as limited enzyme or conjugating agent availability

  
• Genetic factors


  • Variations in an individual's genetic makeup that can influence the activity and expression of biotransformation enzymes
• Genetic variations of CYP450 isoenzymes


  • Genetic variations within the cytochrome P450 (CYP450) enzyme family, which is involved in the metabolism of a wide range of drugs and xenobiotics
• Environmental factors


  • External influences such as diet, exposure to toxins, pollutants, and lifestyle habits that can impact the expression and activity of biotransformation enzymes