Lecture 6 - Pharmacokinetics

• Pharmacokinetics


  What the body does to the drug, including changes in drug concentration over time, how the drug enters the body, where it goes in the body and how the body gets rid of the drug
• Pharmacodynamics


  What the drug and receptor, as well as other effects of the drug
• Stages of drug disposition

  • Absorption from the site of administration
  • Distribution within the body
  • Metabolism
  • Excretion
• Pharmacokinetics approach


  1. Measure the concentration of the drug in plasma

  2. Fit data to theoretical models

  3. Determine parameters such as Cmax and Tmax
• Uses of pharmacokinetics approach

  • Therapeutic efficacy
  • Drug interactions
  • Therapeutic drug monitoring
  • Interpretation and translation of preclinical data
  • Bioavailability and bioequivalence for drug regulators
• Fluid compartments in the body

  • Extracellular fluid (plasma, interstitial fluid, lymph)
  • Transcellular fluid (cerebrospinal, intraocular, peritoneal, pleural, synovial fluids, and digestive secretions)
• Drugs exist in


  Free and bound forms in these compartments
• Factors governing drug distribution

  • Bulk flow (blood, lymphatics, cerebrospinal fluid)
  • Diffusion through cell membranes and epithelial barriers
  • Routes by which solutes cross cell membranes (diffusion directly through lipid, diffusion through aqueous pores, combine with a solute carrier or membrane transporter, and pinocytosis)
• Volume of distribution (Vd)

  The theoretical volume that all the drug would have to occupy if it were present at the same concentration as that found in plasma
• Drugs with low Vd

  Confined to plasma
• Drugs with high Vd


  Equilibrate with tissues
• Drug clearance


  The volume of plasma containing the total amount of drug removed from the body per unit time
• Drug clearance


  The sum of clearance rates for each elimination route, relating the rate of elimination to the drug's plasma concentration
• Single compartment model


  • Assumes the patient is a single well-stirred compartment
• Double compartment model


  • Involves a central (plasma) compartment and a peripheral compartment
• Saturation kinetics


  Disappearance of a drug from plasma is linear, irrespective of dose or concentration
• Volume of distribution (Vd)

  An apparent volume and a measure of how readily drug diffuses out of plasma into tissues
• Calculating Vd


  Vd = amount of drug in body / plasma conc.
• Total clearance of a drug (CLtot)

  The volume of plasma containing the total amount of drug removed from the body per unit time
• Total clearance of a drug (CLtot)

  The sum of clearance rates for each elimination route, relating the rate of elimination to the plasma concentration
• Knowing clearance


  Enables clinicians to calculate the dose rate needed to achieve the desired target steady-state concentration (Css)
• Single compartment model assumes rates of absorption, metabolism, and excretion are directly proportional to drug concentration in the compartment
• Two-compartment model adds a second exponential component to the Cp time course due to drug entering a peripheral compartment from the central (plasma) compartment
• Double exponential kinetics has a fast and slow phase, with the slow phase providing an estimate of kel
• Saturation kinetics apply to drugs where increasing drug concentration increases metabolism, such as ethanol, phenytoin, and salicylate
• Saturation kinetics lead to zero-order kinetics, where disappearance from plasma is linear, irrespective of dose or Cp