L36-37 Drug elimination: metabolism

• IV Bolus


  Intravenous bolus administration of a drug
• Oral


  Oral administration of a drug
• IV Infusion


  Intravenous infusion administration of a drug
• Elimination


  Irreversible loss of drug by excretion and/or metabolism
• Excretion


  Irreversible loss of chemically unchanged drug, mainly by kidneys, also: bile, sweat, saliva, air, milk etc.
• Metabolism


  Conversion of the drug into a different chemical species, mainly by liver, also: lungs, GI wall, blood, skin, kidney
• Understanding elimination of a drug

  • Helps to predict drug concentration following uptake of a medicine
  • Helps to predict how liver and renal disease may affect drug concentration
  • Helps to predict interactions modifying the elimination of drugs
  • Helps to predict variability in drug therapy
• Clearance (Cl)


  The proportionality factor that relates the elimination rate of a drug with the drug concentration in blood (plasma)
• Rate of Elimination= Clearance * Cdrug
• Clearance is the volume of fluid (blood, plasma) that is completely cleared of drug per unit time
• Clearance I > Clearance II

  For the same plasma concentration, the elimination rate is greater for drug I
• Clearance is different for each drug

  Plasma levels decay faster for drug with higher clearance
• Rate in (dose/time)= Rate out (Cl * Css)
• Additivity of Clearance


  The total elimination rate for a drug is the sum of the elimination rates by each organ
• The only exception to the additivity rule is the clearance by the lungs
• Metabolism (biotransformation)


  A defence mechanism against undesirable foreign compounds, including drugs
• The liver is the major site of drug metabolism
• Common routes of drug metabolism

  • Oxidation, reduction, hydrolysis: Phase I reactions
  • Conjugation: Phase II reactions
• Metabolites


  Can be inactive, toxic, or active as the drug administered
• Administration of prodrugs relies on metabolism to form the active compound (the metabolite) from the inactive prodrug
• The liver


  • Receives blood from hepatic artery (25%) and hepatic portal vein from various GI segments (75%)
  • Receives ≈ 1.5 L/min of blood
  • Blood arriving from both systems fuse and enter the liver capillaries called "sinusoids"
  • Blood leaves the liver via the hepatic vein that goes to the vena cava
  • Secretes bile acids, which empty to the common bile duct, and finally go to the gallbladder
  • Excretes and metabolises drugs
• Hepatic elimination processes


  Metabolism + biliary excretion
• Lipophilic chemicals are usually metabolised into more hydrophilic entities and then excreted into urine or bile
• Drugs in blood


  May be bound to plasma proteins, bound to blood cells, or free (unbound)
• Only free drug can enter the hepatocyte to be eliminated
• Enzyme-drug reactions


  Are typically described by the Michaelis-Menten equation
• Drugs metabolised by the same enzyme can be metabolised at different rates
• A drug can be metabolised by several enzymes
• Cytochrome P450 family


  Enzymes responsible for oxidation and reduction of many drugs
• There are other enzymes also involved in drug metabolism
• Substrate specificity


  A drug is normally a good substrate for one (some) enzymes but not for others
• Michaelis-Menten kinetics


  • Elimination rate= Vmax*C/(KM+C)
  • Vmax is the maximum elimination rate
  • KM is the Michaelis constant, the concentration of drug at which the rate equals 1/2 Vmax
• Drug metabolism is saturable: at high concentrations the rate becomes constant and equal to Vmax
• Enzyme-inhibition


  Direct inhibition or by competition
• Enzyme-induction


  A drug or other chemical increases the activity of the enzyme, usually by increasing the amount of enzyme
• Examples of enzyme inducers and inhibitors

  • Inducers: smoking, insecticides, rifampin, phenobarbital
  • Inhibitors: SSRIs, grapefruit
• Variability in drug metabolism

  • Levels and activity of enzymes may differ among individuals resulting in different values of clearance
  • Genetic variations: fast metabolizer, slow metabolizer, ultra-fast metabolizer
  • Age, physio-pathology (hepatic disease)
• Hepatic Extraction Ratio (EH)

  The fraction of a drug passing by the liver which is eliminated (metabolized and/or excreted into bile) by this organ
• EH can range from 0 (no elimination) to 1 (complete elimination)
• Hepatic Clearance (ClH)


  The volume of blood entering the liver from which all the drug is removed per unit time