Metabolism

Drug Metabolism

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Drug Metabolism, Medication Kinetics, Drug Kinetics, Drug Pharmacokinetics, Pharmacokinetics, Absorption Distribution Metabolism Excretion, ADME, Renal Drug Elimination, Renal Medication Excretion, Renal Clearance, Hepatobiliary Drug Elimination, Hepatobiliary Medication Excretion, Hepatic Clearance, Metabolic Clearance Rate, Biological Availability, Bioavailability, Half-Life, Distribution Half Life, Elimination Half-Life, Bioavailable

  • See Also
  1. Drug Interaction
  2. Drug Route
  3. Cytochrome P450
  • Definitions
  1. Pharmacokinetics (or kinetics)
    1. Absorption, Distribution, Metabolism and Excretion (ADME)
  2. Biological Availability (Bioavailability)
    1. Rate and amount of drug absorption into the bloodstream and distribution to tissues
    2. Measured by serum concentrations or by pharmacologic or therapeutic response
  3. Metabolic Clearance Rate
    1. Rate that a drug and its metabolites are cleared from tissue and body fluids
    2. Drug elimination is chiefly via renal and Hepatic Clearance
  4. Renal Elimination
    1. Drug clearance via the Kidney and urine
  5. Hepatic Elimination
    1. Drug clearance via the liver, biliary tract and intestinal tract
  6. First Pass Effect (First Pass Metabolism)
    1. Drugs taken orally must first pass through the liver where they may be metabolized to inactive forms (reducing their Bioavailability)
  7. Half-Life (T1/2)
    1. Time required for a drug's plasma concentration to drop 50% after discontinuation
  8. Distribution Half Life (T1/2a)
    1. Time required for a drug's plasma concentration to drop 50% as it distributes to body tissues (typically rapid over minutes)
  9. Elimination Half-Life (T1/2b)
    1. Time required for half of a drug to be metabolized and excreted (typically slow over hours)
  10. Steady State
    1. Plasma concentration that is consistent (continuous IV infusion) or fluctuating in a consistent range (intermittent dosing)
    2. Drugs reach their steady state (plasma concentration, peak or trough) typically after 4-5 drug half-lives
  • Types
  • Proteins that increase drug water solubility and in turn aid elimination
  1. Cytochrome P450
    1. Enzymes: CYP1A2, CYP2C9, CYPC19, CYP2D6, CYP2E1, CYP3A4
  2. Uridine Diphosphate-glucuronosyltransferase (UGT) Conjugating Enzyme
    1. Glucuronosyltransferases perform Glucuronidation primarily in the liver and aid drug excretion
  • Types
  • Transport Proteins move drugs and metabolites from one body compartment to another
  1. Adenosine Triphosphate binding casette (ABC) drug uptake/efflux transporters
    1. Enzymes: Efflux pump P-Glycoprotein (P-gp)
  2. Organic anion-transporting polypeptide (OATP) drug transporters
    1. Enzymes: OATP1A1, OATP1A2, OATP2B1
  • Dosing
  1. Single dose
    1. Drug reaches a peak plasma concentration after full absorption or infusion
    2. Plasma levels typically fall at a consistent linear rate as tissue distribution, metabolism and excretion occur
  2. Continuous IV infusion
    1. Drugs reach their steady state plasma concentration after 4-5 drug half-lives
    2. Increased infusion rate raises the plasma concentration but does not decrease the time to steady state
  3. Intermittent dosing
    1. Drugs reach their steady state (fluctuation between consistent peak or trough) typically after 4-5 drug half-lives
    2. Peak
      1. High point of drug plasma concentration
      2. Drug toxicity is more likely to occur at peak drug concentration
    3. Trough
      1. Low point of drug plasma concentration
      2. Inadequate drug effect is more likely to occur at trough concentration
    4. Loading dose
      1. Drug loading doses (higher initial dose or doses) may be given to reach higher early therapeutic peak plasma concentrations
      2. Subsequent maintenance doses follow loading doses
      3. Time to steady state is not affected by the loading dose, and still depends solely on drug Half-Life
    5. Onset of Drug Activity
      1. Onset of therapeutic drug effect
      2. Primarily affected by Drug Administration Route (e.g. slow via oral route, rapid via IV)
    6. Duration of Drug Activity
      1. Duration of therapeutic drug effect
      2. Most influenced by a drug's Half-Life, although other factors (e.g. prolonged receptor binding) may extend activity duration
  • Physiology
  • Pharmacokinetics
  1. Absorption
    1. Bioavailability of a drug is dependent on absorption of that drug across multiple membrane surfaces
      1. Passive diffusion allows for small, lipophilic, nonionic molecules to rapidly cross membranes, following a concentration gradient
      2. Facilitated diffusion relies on carrier molecules to cross membranes
      3. Aqueous channels allow small (MW <200), hydrophilic molecules to cross membranes, following a concentration gradient
      4. Active transport requires both a carrier molecule (facilitated) and ATP for specific drugs to cross membranes, against a gradient
    2. Absorption is dependent on multiple drug characteristics (polarity, size, solubility, formulation)
      1. Small, nonionized, lipid soluble drugs have the highest absorption (most membrane permeable)
    3. Patient factors impact absorption (e.g. GI Tract perfusion, Stomach acidity, interacting ingested substances including food)
  2. Distribution
    1. Apparent Volume of Distribution (Vd)
      1. Calculated volume needed to contain the total administered drug at the same measured plasma concentration
      2. Vd indicates the degree of tissue distribution of a drug compared with its plasma distribution (volume of plasma in adults)
        1. Drugs limited to plasma distribution would have a Vd = 3 Liters
        2. Drugs limited to extracellular compartment would have a Vd = 16 Liters (plasma and interstitial fluid)
        3. Drugs with very large Vd (e.g. >46 liters, greater than Total Body Water) suggest a drug depot effect
    2. Membrane permeability
      1. Small, lipophilic drugs may rapidly cross intestinal lining, capillary walls and the blood brain barrier
      2. Other drugs may fail to cross key membranes
        1. Blood brain Barrier (differentiates drugs with CNS effects)
        2. Blood-placenta Barrier (differentiates drugs considered safe in pregnancy)
        3. Blood to Breast Milk Barrier (differentiates drugs considered safe in Lactation)
        4. Blood-Testes Barrier
    3. Plasma Protein binding
      1. Protein-bound drugs (e.g. albumin bound) are typically inactive and not distributed to organs and tissue
      2. Free drug concentrations are key to the drugs distribution and activity
    4. Depot Storage
      1. Lipophilic drugs may accumulate in fat and result in prolonged effects
      2. Drugs that bind Calcium may accuulate in bone and teeth
  3. Metabolism
    1. Drug Metabolism typically results in a more polar (and more water soluble) drug
    2. Prodrugs (inactive or less active) must be metabolized to their active drug forms
      1. Prodrug examples include Clopidogrel, Prednisone, valacylovir
    3. Many, less polar drugs require metabolism before they are able to be excreted
      1. Polar drugs (e.g. Gentamicin, Digoxin) do not require metabolism before excretion
    4. Reaction Phases
      1. Phase 1 Reaction (non-synthetic)
        1. See Redox Reaction
        2. Oxidation or reduction of a drug into a more polar form
      2. Phase 2 Reaction (synthetic)
        1. Polar group is conjugated to the drug, resulting in a highly polar agent
    5. Cytochrome P450 System
      1. Hepatocytes in the liver contain a P450 family of microsomal enzymes on the endoplasmic reticulum
      2. P450 Enzymes facilitate drug oxidation and reduction, utilizing NADPH donated electrons (Phase 1 Reaction)
  4. Excretion
    1. Most drugs (90%) require metabolism to more polar and water soluble agents before excretion
    2. Majority of drugs are excreted in the urine
      1. Renal dysfunction may be associated with drug accumulation
    3. Urine excretion depends on glomerular filtration, tubular secretion and tubular reabsorption
      1. Glomerular Filtration allows easy passage of small non-ionic drugs, but typically blocks Protein-bound drugs
      2. Tubular secretion requires active transport of specific drugs competing for carrier binding sites
      3. Tubular reabsorption is typically of small nonionic drugs, which may result in their lower excretion rates
        1. Ionic drugs are poorly reabsorbed and typically have higher excretion rates
    4. Some drugs are excreted in stool (may be concentrated in bile)
      1. Enterohepatic circulation may result in prolonged drug effects after a drug is reabsorbed after excretion
  5. Clearance
    1. Clculated rate that a drug and its metabolites are cleared from tissue and body fluids
    2. Drug Clearance (L/h) = ElimRate / DrugConc
      1. Where ElimRate = Elimination Rate (mg/h)
      2. Where DrugConc = Drug Concentration (mg/L)
      3. Drug Clearance is measured in L/h (contrast with Rate of Elimination, measured in mg/h)
  • Physiology
  • Drug Dependency
  1. Drug Tolerance
    1. Drug dosing needs to be increased to maintain the same prior effect
    2. Mechanisms
      1. Metabolic (Drug Metabolism is upregulated as dosing is increased)
      2. Cellular (drug receptors are down regulated)
    3. Examples: Alcohol Tolerance
      1. Blood Alcohol Level falls 0.03/h in Alcoholics compared with 0.02/h in others
  2. Drug Dependence
    1. See Chemical Dependence
    2. Drug is required by patient to maintain normalcy (often with withdrawal symptoms when that drug is stopped)
    3. Examples: Alcohol Dependence, Benzodiazepine Dependence
  3. Drug Withdrawal
    1. Drug stoppage results in exaggerated symptoms
    2. Examples: Alcohol Withdrawal, Opioid Withdrawal, Antidepressant Withdrawal
  • Physiology
  • Patient Factors
  1. See Medications in Pregnancy
  2. See Medications in Lactation
  3. See Drug Activity in Women
  4. See Medication Use in the Elderly
  5. See Polypharmacy
  6. See Drug Dosing in Chronic Kidney Disease
  7. See Genetic Determinants of Drug Response
  8. See Key Potentially Inappropriate Drugs in Pediatrics
  • References
  1. Olson (2020) Pharmacology, Medmaster, Miami, p. 1-12
  2. Asher (2017) Am Fam Physician 96(2): 101-7 [PubMed]